Published May 2016

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NOTE: Part 1 is originally published with the lipid association.

Prepared by Harold Bays, M.D., F.T.O.S., F.A.C.C., F.A.C.E., F.N.L.A., Shanu N. Kothari, M.D., F.A.C.S., F.A.S.M.B.S., Dan E. Azagury, M.D., Ninh T. Nguyen, M.D., F.A.C.S., F.A.S.M.B.S., Terry A. Jacobson, M.D., F.A.C.P., F.N.L.A., Carl Orringer, M,D., Deborah B. Horn, D.O., M.P.H., Diplomate A.B.O.M., John M. Morton, M.D., M.P.H., F.A.C.S., F.A.S.M.B.S., Eric C. Westman, M.D., M.H.S., Diplomate A.B.O.M., Peter H. Jones, M.D., F.N.L.A., David E. Cohen, M.D., Ph.D., Wendy Scinta, M.D., M.S., Craig Primack, M.D., F.A.C.P., F.A.A.P., Diplomate A.B.O.M.


Abstract: Bariatric procedures generally improve dyslipidemia, sometimes substantially so. Bariatric procedures also improve other major cardiovascular risk factors. This 2-part Scientific Statement examines the lipid effects of bariatric procedures and reflects contributions from authors representing the American Society for Metabolic and Bariatric Surgery (ASMBS), the National Lipid Association (NLA), and the Obesity Medicine Association (OMA). Part 1 was published in the Journal of Clinical Lipidology, and reviewed the impact of bariatric procedures upon adipose tissue endocrine and immune factors, adipose tissue lipid metabolism, as well as the lipid effects of bariatric procedures relative to bile acids and intestinal microbiota. This Part 2 reviews: (1) the importance of nutrients (fats, carbohydrates, and proteins) and their absorption on lipid levels; (2) the effects of bariatric procedures on gut hormones and lipid levels; (3) the effects of bariatric procedures on nonlipid cardiovascular disease (CVD) risk factors; (4) the effects of bariatric procedures on lipid levels; (5) effects of bariatric procedures on CVD; and finally, (6) the potential lipid effects of vitamin, mineral, and trace element deficiencies, that may occur after bariatric procedures. (Surg Obes Relat Dis 2016;12:468–495.) (r) 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.


Bariatric procedures generally improve dyslipidemia, sometimes substantially so. Part 1 of this 2-part scientific statement provided an overview of: (1) adipose tissue, cholesterol metabolism, and lipids; (2) bariatric procedures, cholesterol metabolism, and lipids; (3) endocrine factors relevant to lipid influx, synthesis, metabolism, and efflux; (4) immune factors relevant to lipid influx, synthesis, metabolism, and efflux; (5) bariatric procedures, bile acid metabolism, and lipids; and (6) bariatric procedures, intestinal microbiota, and lipids, with specific emphasis on how the alterations in the microbiome by bariatric procedures influence obesity, bile acids, and inflammation, which in turn may all affect lipid levels.

Part 2 of this scientific statement reviews: (1) the importance of nutrients (fats, carbohydrates, and proteins) and their absorption on lipid levels; (2) the effects of bariatric procedures on gut hormones and lipid levels; (3) the effects of bariatric procedures on nonlipid cardiovascular disease (CVD) risk factors; (4) the effects of bariatric procedures on lipid levels; (5) effects of bariatric procedures on CVD; and finally (6) the potential lipid effects of vitamin, mineral, and trace element deficiencies that may occur after bariatric procedures.

Bariatric procedures, intestinal nutrient metabolism, and lipids

General nutritional considerations

Bariatric procedures may affect gut hormones, which are important for nutrient digestion and metabolism, which in turn may affect lipid levels. Both the quantity and quality of foods (e.g., fats, carbohydrates, proteins, vitamins, minerals, trace elements, and other chemical compounds) can influence adipocyte and adipose tissue function. Metabolic diseases (including dyslipidemia) [1–3] are affected by bariatric procedures.

Fats are organic compounds that include cholesterol (see Part 1 of this Scientific Statement) and triglycerides. Triglycerides are composed of 3 fatty acids attached to a glycerol backbone, which may be saturated (no double bonds) or unsaturated (1 or more double bonds). The fatty acid components of triglycerides are mostly 4–28 carbons long. In adipose tissue, stored triglycerides usually have fatty acid components 12–24 carbons long and 0–6 double bonds. The fatty acids perhaps most easily mobilized from adipocytes by hormone-sensitive lipase are fatty acids that are shorter and more unsaturated (e.g., highly mobilized fatty acids include 16–20 carbon fatty acids with 4–5 double bonds; weakly mobilized fatty acids include 20–24 carbon fatty acids with 0–1 double bond) [4]. Dietary fats are energy-dense foods, with fat generating 9 calories per gram, carbohydrates 4 calories per gram, proteins 4 calories per gram, and alcohol 7 calories per gram. After undergoing emulsification by bile secreted by the liver and gallbladder, most dietary fats are absorbed in the small intestine.

Carbohydrates are chain or ring structures composed of 1 carbon per 2 hydrogens per 1 oxygen and include: (1) simple sugars often utilized for short-term cellular energy (i.e., monosaccharides such as glucose, fructose, and galactose, as well as disaccharides such as sucrose, maltose, and lactose); (2) complex carbohydrates for intermediate energy storage (i.e., plant starches composed of long polymers of glucose molecules with bond attachments in the same direction, and animal glycogen composed of polymers of glucose molecules with branching structure); and (3) polysaccharide cellulose composed of long polymers of glucose molecules with bond alternating in opposite directions, which provides structural support for plant cell walls and which represent “dietary fiber.” After enzymatic digestion of complex carbohydrates beginning in the mouth, and after further metabolism occurring in the small intestine, simple sugars are absorbed in the small intestine. In humans, dietary fiber usually passes through the intestine without significant digestion. As noted in Part 1 of this Scientific Statement, certain bacteria microbiota (e.g., phyla Firmicutes) can at least partially digest fibers into short chain fatty acids, which may be absorbed by the intestine, thus enhancing body energy/calorie absorption [5].

Proteins are linear chain compounds, folded into a tertiary or quarternary structure composed of nitrogen-containing amino acids. After undergoing digestion in the stomach by gastric juices, proteins are absorbed in the small intestine as amino acids. Different proteins may differ in their effects on adipocyte function and insulin secretion [1].

Dietary quantity can affect lipid blood levels [2,3,6,7]. Especially in patients with dyslipidemia caused by adiposo- pathic consequences of obesity, fat weight loss may be the most important factor in improving dyslipidemia, relative to the types of nutrients consumed. At least within the first year or so, regarding food quality: (1) Restricting saturated fats and transfats may reduce low-density lipoprotein (LDL) cholesterol levels; (2) restricting carbohydrates (especially carbohydrates with high glycemic index and load) may reduce triglyceride and increase high-density lipoprotein (HDL) cholesterol levels; and (3) if substituted for simple carbohydrates and saturated/transfats, increasing the proportion of protein food intake may: (a) improve adipocyte and adipose tissue function, (b) increase satiety and promote thermo- genesis, (c) preserve muscle mass, particularly in older individuals, (d) favorably affect metabolic parameters, and (e) improve dyslipidemia [1,3,8,9]. To the extent bariatric procedures alter the quantity and quality of intestinal nutrient absorption [10], then alterations in macronutrients and micronutrients may affect lipid levels. Therefore, to better understand how bariatric procedures might affect metabolic disease such as dyslipidemia, it is important to understand nutrient metabolism. Part 1 of this Scientific Statement provided details regarding the clinical relevance of enzymes, systemic hormones, inflammation mediators, and other factors relative to adipocyte and adipose tissue function, and the effect of bariatric surgery on these factors with respect to dyslipidemia. The following background discussion on nutrient digestion and metabolism in this Part 2 specifically focuses on the effects of bariatric procedures on gut hormones (Fig. 1; Table 1) [3,11–53] and how affected gut hormones may influence lipid blood levels.

Intestinal fat metabolism

More than 90% of consumed fats are triglycerides. Upon entering the small intestine, dietary fats stimulate duodenal cholecystokinin release (Fig. 1; Table 1) [3,11–53], facilitating bile release from the gallbladder and liver, as well as lipase, cholesteryl esterase, and phospholipase release from the pancreas. After triglycerides undergo emulsification by bile salts, pancreatic and intestinal lipases hydrolyze the triglycerides. Digested triglycerides are absorbed into the small intestine as free fatty acids and monoglycerides in the duodenum, with a small fraction absorbed as free glycerol and diglycerides. Once absorbed in intestinal cells, free fatty acids and glycerol are re-esterified into triglycerides and then packaged with re-esterified cholesterol into apoB48-containing chylomicrons. Chylomicrons enter mesenteric lymph vessels and eventually are introduced into the circulation, where they bind to peripheral tissues such as membranes of hepatocytes, adipocytes, and myocytes. Increased hepatic delivery of triglyceride-containing saturated fatty acids or trans-fatty acids may result in hepatosteatosis, and increased very low density lipoprotein (VLDL) secretion, potentially resulting in hypertriglyceridemia [54]. It is unclear that hepatic delivery of monounsaturated fats increase hepatosteatosis or VLDL secretion. Polyunsaturated omega-3 fatty acids may actually decrease hepatosteatosis and may decrease hepatic VLDL secretion, reducing triglyceride levels [55].

During periods of fasting, when body tissue energy is needed, triglycerides stored in adipocytes undergo lipolysis by hormone-sensitive lipase, generating the release of free or nonesterified fatty acids in to the circulation, which are complexed and carried by plasma proteins (i.e., albumin). Free fatty acids are the major secretory product of adipose tissue. Once these circulating free fatty acids are delivered to tissues such as muscle and liver, they may become activated in the intracellular cytosol by binding to coenzyme A, wherein they are then transported to the mitochondria via carnitine, undergo β-oxidation, and ultimately generate acetyl-CoA. Acetyl-CoA enters the tricarboxlic acid cycle (i.e., citric acid cycle or Krebs cycle) to generate adenosine triphosphate, which is the intracellular transporter of chemical energy.

Two of the more sentinel lipases involved with fat metabolism include hormone-sensitive lipase and lipoprotein lipase. Hormone-sensitive lipase is an intracellular, rate-limiting enzyme highly expressed in adipocytes that hydrolyzes cholesteryl esters to free cholesterol and hydrolyses triglyceride esters into free fatty acids and diglycerides. Adipocyte triglyceride lipase also hydrolyzes triglycerides; adipocyte triglyceride lipase and hormone-sensitive lipase are responsible for more than 95% of triglyceride hydrolase activity in white adipose tissue [3]. Diglycerides are rapidly metabolized by diglyceride lipase to a monoglycerides, with the remaining fatty acid cleaved from the glycerol backbone by monoglyceride lipase. Hormone-sensitive lipase is the lipolytic enzyme most affected by hormones. Hormone-sensitive lipase is downregulated by insulin hormone, with hyperinsulinemia being anabolic in promoting triglyceride storage in adipocytes. Conversely, hypoinsulinemia increases hormone-sensitive lipase activity, catalyzing intracellular triglycerides into fatty acids. Hormone-sensitive lipase is also upregulated with catecholamines (i.e., β-adrenergic stimulation) and adrenocorticotropic hormone (ACTH). Increased stress responses via sympathetic nervous system and ACTH and decreased insulin levels are thus both catabolic in promoting triglyceride breakdown and, ultimately, facilitating adipose tissue release of fatty acids into the circulation.

Lipoprotein lipase is another important lipase enzyme that is produced and secreted by adipocytes into extracellular surroundings. Lipoprotein lipase serves to hydrolyze triglycerides found in circulating lipoproteins into glycerol and free fatty acids. Because adipocytes do not synthesize fatty acids, adipocytes rely on acquiring extracellular fatty acids generated by lipoprotein lipase interaction with lipoproteins for intra-adipocyte lipogenesis. In the postprandial state, lipoprotein lipase interacts with chylomicrons (as well as other triglyceride-rich lipoproteins, such as VLDL and intermediate-density lipoproteins [IDL]). In the fasting state, lipoprotein lipase mainly interacts with VLDL and other triglyceride-rich lipoproteins. Once extracellular triglycerides are hydrolyzed by lipoprotein lipase, free fatty acids undergo transport via fatty acid transport protein into adipocytes.

Fig. 1. Gastrointestinal hormones help regulate caloric balance, food digestion, and nutrient utilization. After fasting and before eating, gastrointestinal hormones may increase hunger (e.g., ghrelin and neuropeptide Y). After eating, gastrointestinal hormones may (1) decrease hunger/promote satiety (e.g., somatostatin, cholecystokinin, motilin, insulin, glucagon, pancreatic polypeptide, amylin, fibroblast grown factor 19, glucagon like peptide-1, oxyntomodulin, and peptide YY); (2) help manage digestion through slowing gastric motility/emptying (e.g., cholecystokinin, amylin, glucagon like peptide-1, oxyntomodulin, and peptide YY) (3) stimulate the release of digestive enzymes (e.g., gastrin, cholecystokinin, secretin); (4) have counter-regulatory functions in impairing digestive enzyme release (e.g., somatostatin, secretin, pancreatic polypeptide, glucagon like peptide 2, oxyntomodulin, peptide YY); and/or may assist with postabsorptive systemic nutrient management after digestion (e.g., somatostatin, insulin, glucagon, fibroblast growth factor 19). *Neuropeptide Y (NPY) is a member of the pancreatic polypeptide-peptide family, expressed at all levels of the gut. NPY is also produced in the brain, and is the most abundant neuropeptide in the brain, involved with appetite and pain sensation functions.

Afterward, free fatty acids undergo activation by CoA, which is an esterification process required for fatty acid oxidation, synthesis of triglycerides, or attachment to proteins. The 3-carbon glycerol for which the 3 activated fatty acids are attached in forming triglycerides originates from glucose or pyruvate. Thus, adipocytes must have access to both free fatty acids and glucose to store fatty acids as triglycerides. Through a number of enzymatic steps involving the formation of lysophatidic acid (one fatty acid), and then phosphatidic acid and diacylglycerol (both 2 fatty acids), glycerol-3-phosphate may ultimately be esterified with 3 fatty acids (often mixed in size) through the terminal enzymatic step involving diacylglycerol acyltransferase (DGAT). In addition to hormones (similar to hormone-sensitive lipase), lipoprotein lipase activity may also be affected by apolipoproteins and drugs. Although insulin may decrease hormone-sensitive lipase (limiting fatty acid release from adipocytes), insulin increases lipoprotein lipase activity, which reduces triglyceride blood levels. Apolipoprotein C-III (ApoC-III) is a small protein that resides on triglyceride-rich VLDL and chylomicron particles that inhibits lipoprotein lipase, impairs hepatic uptake of triglyceride-rich lipoproteins (e.g., lipoprotein remnants), contributes to insulin resistance, and generally promotes elevated triglyceride levels. Fibrates and omega-3 fatty acids are lipid-altering pharmacotherapies that reduce ApoC-III levels, increase lipoprotein lipase activity and thus lower triglyceride blood levels.

The hormone effects on hormone-sensitive lipase and lipoprotein lipase affect circulating free fatty acid levels. After meals, circulating free fatty acids are dramatically decreased (by 70%–90%), substantially as a result of increased insulin levels, which upregulate lipoprotein lipase and downregulate hormone-sensitive lipase, reducing triglyceride blood levels, increasing transport of fatty acids into fat cells, and “trapping” fatty acids in the form of intracellular triglycerides (because of reduced intracellular triglyceride lipase activity). During fasting, decreased insulin levels downregulate lipoprotein lipase and upregulate hormone-sensitive lipase, and increase the release of free fatty acids from adipocytes into the circulation. These circulating free fatty acids may undergo β-oxidation by muscle for energy or undergo hepatic β-oxidation, ketogenesis, lipogenesis, and gluconeogenesis. Prolonged fasting for longer than 7 days may markedly increase circulating free fatty acids, resulting in hepatosteatosis, ketosis, and insulin resistance and potentially a rise in triglyceride blood levels.

Especially if adipocytes have adiposopathic impairment of adipogenesis and function, then during times of positive caloric balance, free fatty acids not stored in adipocytes and may be shunted to other body tissues, such as the liver, muscle, and pancreas. This may result in “lipotoxicity,” which is the dysfunction of body organs promoted by deposition of excessive free fatty acids and their products (e.g., ceramides and diacylglycerols). Lipotoxicity may result in hepatic and muscle insulin resistance, potential insulinopenia from the pancreas, and dysfunction of other body organs (e.g., the heart, vasculature, kidney). Patients with type 2 diabetes often have increased circulating fasting and postprandial free fatty acids compared with those without type 2 diabetes, and also often have increased insulin resistance and decreased pancreatic insulin release relative to glucose levels. In summary, elevated circulating free fatty acids may contribute to “lipotoxicity.” The levels of free fatty acids in the circulation can be attributable to: (1) postprandial or fasting state; (2) adipose tissue storage capacity; and (3) the degree by which other body organs either store free fatty acids as triglycerides or metabolize free fatty acids. The processes involved in intestinal fat metabolism are dependent on intestinal digestion and gut hormones. Table 1 describes bariatric procedure effects on gut hormones important for fat and lipid digestion, which may influence lipid levels [3,11–53].

Intestinal carbohydrate metabolism

Monosaccharides can be directly absorbed through the mouth mucosa (e.g., therapeutic use of oral glucose agents to treat hypoglycemia), whereas consumed plant starches and animal glycogen must undergo digestion from chewing and salivary gland amylase, which begins to hydrolyze these complex carbohydrates to more simple sugars. Once in the small intestine, chyme (the acidic gastric juices and partially digested food) promotes release of cholecystokinin by small intestine L-cells, causing the release of bile from the gallbladder, as well as digestive juices from the pancreas, which include: (1) lipase, cholesteryl esterase, and phospholipase for fat digestion; (2) trypsin, chymotrypsin, and carboxypolypeptidase for protein digestion; and (3) amylase, which further catalyzes the hydrolysis of complex carbohydrates (e.g., starches and glycogen, not cellulose) to more simple sugars (Fig. 1; Table 1) [3,11–53]. Afterward, monosaccharides (e.g., glucose, fructose, galactose) are mostly absorbed across the brush border of the small intestine by transporters, such as facilitative passive hexose glucose transporters (e.g., GLUT-2, GLUT-5, etc.) or active sodium-coupled glucose cotransporters (e.g., SGLT-1, etc.) [56]. The major circulatory hexose transporter found in adipocytes and muscle is GLUT-4, which is regulated by insulin. Once delivered to the liver or muscle, fructose and galactose are converted to glucose. Once glucose is phosphorylated, it may interact with uridine triphosphate to form uridine diphosphate glucose, which allows for linkage to other glucose and, ultimately, glycogen formation. Lipogenesis is limited in muscle. In the liver, if glycogen stores are replete, then an increased dietary consumption of carbohydrates may increase circulating insulin and glucose and, through SREBP-1–mediated increase in lipogenic gene expression, increase fat storage in the liver. In adipocytes, the increase in circulating insulin and glucose from consumption of carbohydrates may promote peroxisome proliferator activated receptor γ–mediated lipogenic gene expression. Although not clear that simple sugars differ in their potential adverse health effects when evaluated in the manner typically consumed, and at typical amounts in the human diet [57], fructose (such as from high-fructose corn syrup) is often described as especially promoting fatty liver, obesity, and insulin resistance [58]. The processes involved in carbohydrate metabolism are dependent on intestinal digestion and gut hormones. Table 1 describes bariatric procedures’ effects on gut hormones important for carbohydrate digestion, which may influence lipid levels [3,11–53].

Intestinal protein metabolism

Proteins are metabolized in the stomach by gastric acid (hydrochloric acid, potassium chloride, and sodium chloride) ecreted by stomach parietal cells, which breaks down proteins into amino acids. Other stomach epithelial lining cells produce gastric pepsin (most active at low pH), which breaks down collagen, the main structural protein found in animal connective tissue. Once in the small intestine, cholecystokinin-mediated release of trypsin, chymotrypsin, and carboxypolypeptidase (Fig. 1; Table 1) [3,11–53] from the pancreas continues to hydrolyze proteins into amino acids, which are then absorbed into circulation (Fig. 1; Table 1) [3,11–53]. Once delivered to the liver, surplus amino acids undergo deaminization and are converted into glucose via the alanine cycle. Nitrogen from the amine group of amino acids is converted to urea (e.g., urea cycle), which is excreted by the kidney. The carbon components of amino acids may also be converted to keto acids, giving rise to acetyl-CoA and generation of fatty acids for lipogenesis. The processes involved in intestinal protein metabolism are dependent on intestinal digestion and gut hormones. Table 1 describes bariatric procedures’ effects on gut hormones important for protein digestion, which may influence lipid levels [3,11–53].

Bariatric procedures and nonlipid atherosclerotic cardiovascular disease risk factors

Patients with obesity are at increased risk for cardiovascular disease [59]. Improvement in dyslipidemia is an important health benefit of bariatric procedures, helping to account for a reduction in CVD risk. However, bariatric procedures reduce multiple CVD risk factors [60]. Table 2 lists a number of CVD disorders caused by adiposopathy [61]. Table 3 describes the potential effects of bariatric procedures on atherosclerotic cardiovascular disease (ASCVD) risk factors, as well as adiposopathic markers that may contribute to metabolic disease, most of which are ASCVD risk factors [62–117].

Bariatric procedures and dyslipidemia

Lipids and atherosclerosis

An increase in atherogenic lipoprotein particle number is a root cause of atherosclerosis [118,119]. Lipoprotein concentration can be measured directly [120] or via the surrogate measure of apolipoprotein B (apoB), wherein 1 molecule of apoB resides on every atherogenic lipoprotein [120,121]. ApoB is thus a measure of the concentration of cholesterol-containing atherogenic lipoproteins such as LDL, VLDL, IDL, and VLDL remnants. The cholesterol carried by these atherogenic lipoproteins is termed atherogenic cholesterol, even as it is recognized that apoB–containing and cholesterol-containing lipoproteins themselves more precisely promote atherosclerosis [118,119].

Multiple epidemiologic studies have long supported the “cholesterol hypothesis.” An increase in atherogenic cholesterol increases ASCVD risk, and a decrease in atherogenic cholesterol reduces ASCVD risk [118]. The 2013 National Lipid Association Consensus Statement on the lipid effects of obesity noted that adipocytes and adipose tissue store the greatest amount of body lipids, including triglycerides and free cholesterol [3]. This Consensus Statement also acknowledged that adipocytes and adipose tissue have active endocrine and immune functions, whose disruption results in adiposopathy. Among the cellular findings of adiposopathy include adipocyte hypertrophy (potentially resulting in dysfunction of intracellular organelles such as mitochondria and endoplasmic reticula), growth of adipose tissue beyond its vascular supply (potentially contributing to adipocyte and adipose tissue hypoxia), increased number of adipose tissue immune cells (increasing the potential for proinflammatory responses, such as increased tumor necrosis factor, interleukin-6, and C-reactive protein), and ectopic fat deposition in nonadipose body organs (e.g., liver and muscle). If peripheral subcutaneous adipose tissue storage is limited, then positive caloric balance may also result in “energy over-flow” to other fat depots, such as visceral, pericardial, perivascular, and other periorgan fat. Thus, during positive caloric balance, the limitation in energy (i.e., fat) storage in peripheral subcutaneous tissue combined with an increase in fat deposition in other fat depots helps explain why visceral adiposity might be considered a surrogate marker for global fat dysfunction and why central obesity is a clinical marker of adiposopathy [7].

Adiposopathy (“adipose-opathy,” or “sick fat”) is defined as pathologic adipose tissue anatomic and functional disturbances promoted by positive caloric balance in genetically and environmentally susceptible individuals that results in adverse endocrine and immune responses, which in turn may promote metabolic diseases (e.g., dyslipemia, hyperglycemia, high blood pressure, etc.) and cardiovascular “Malabsorptive” surgical procedures are often described to represent “metabolic surgeries,” in that such procedures may alter gastrointestinal hormonal secretions and favorably influence intestinal bile acids, microbiota, and intestinal gluconeogenesis, which all may contribute to improvement in metabolic diseases, possibly independent of weight loss [65,124]. However, laparoscopic Roux-en-Y gastric bypass (sometimes considered “malabsorptive”) and sleeve gastrectomy (sometimes considered “restrictive”) may have similar degrees of weight loss and improved metabolic health outcomes (e.g., dyslipidemia, diabetes mellitus, high blood pressure) [125,126]. Given the similarities in weight loss and metabolic outcomes with the “malabsorptive” laparoscopic Roux-en-Y gastric bypass and the “restrictive” sleeve gas- trectomy bariatric procedures, all common bariatric procedures might best be considered “metabolic” surgical procedures. That is because the most consistent and unifying aspect of all of these common bariatric procedures is the reduction in body fat, which improves adipocyte and adipose tissue function, and which in turn improves metabolic disease [122]. Thus, the choice of the preferred bariatric procedures for metabolic diseases (including dyslipidemic patients with overweight or obesity) is best determined by the anticipated risks and benefits, expertise of the surgeon and affiliated facility, as well individual characteristics and preferences of the patient. Another consideration is comparative health metabolic outcomes (e.g., dyslipidemia, type 2 diabetes mellitus, hypertension) wherein gastric bypass (“malabsorptive”) may have improved long-term metabolic outcomes compared with gastric banding (“restrictive”) [63]. What may be less important in the bariatric procedure selection is the somewhat artificial and perhaps unhelpful “restrictive” versus “malabsorptive” label, at least with respect to comparisons of the expected weight loss and metabolic effects of laparoscopic Roux-en-Y gastric bypass versus sleeve gastrectomy.

Bariatric procedures and lipid effects

Table 4 describes the effects of various bariatric procedures on lipid parameters [81,107,127–149]. Some observations include the following:

  1. The greater the fat mass loss, the greater the improvement in dyslipidemia. According to the 2014 Cochrane Collaboration update on surgery for weight loss in adults [125], compared with nonsurgical interventions, bariatric surgery results in greater improvement in weight loss adverse health consequences, regardless of the type of procedures used. In general, weight loss is similar between Roux-en-Y gastric bypass and sleeve gastrectomy, with both promoting greater weight loss than adjustable gastric banding. For patients with very high body mass index, biliopancreatic diversion with or without duodenal switch may result in greater weight loss than Roux-en-Y gastric bypass. Many of the reports referenced in Table 4 [81,107,127–149] are consistent with the notion that the greater the fat mass loss, the greater the improvement in lipid (and other metabolic) parameters [150], as often occurs with the more “malabsorptive” procedures [151,152]. Table 4 [81,107,127–149] escribes the major lipid parameters most often reported as improved and includes reductions in LDL cholesterol, total cholesterol, and triglyceride levels, as well as (after 6 mo or so), increases in HDL cholesterol.

  2. Data regarding the lipid effects of biliopancreatic diversion/duodenal switch are less reported than with laparoscopic gastric banding, Roux-en-Y gastric bypass, and sleeve gastrectomy, probably because it is a less common bariatric procedure.

  3. Bariatric procedures allow for a decrease in the use of drugs for treatment of dyslipidemia [127,153], as well as a decrease in drugs used for treatment of diabetes mellitus and blood pressure, compared with medical therapy for obesity [154,155]. Thus, not only are bariatric surgeries superior to medical management in improving metabolic parameters among patients with obesity, but bariatric procedures often allow for less polypharmacy postoperatively. This may allow for both improved lipid levels and reduced lipid-altering drug therapies [156].

  4. HDL cholesterol may decrease during active weight loss (particularly the first 6 mo after bariatric surgery) and then may ultimately increase above baseline. The potential for an initial reduction in HDL cholesterol levels during active weight loss is a well-known phenomenon in clinical lipidology, occurring not only with bariatric procedures, but also some weight management pharmacotherapies, as well as nutritional weight loss—especially with fat-restricted nutritional intervention [3]. As per Part 1 of this Scientific Statement, human trials suggest that within the first 6 months during rapid weight loss with bariatric surgery, both HDL and apoE decrease. The initial drop in HDL cholesterol levels may reflect the gradual qualitative switch of HDL from apoE-containing to more functional apoAI-containing HDL particles [128,157,158].

One of the primary, if not the primary, lipid treatment target is non-HDL cholesterol, which includes the cholesterol carried by all atherogenic lipoproteins (e.g., the cholesterol carried by low-density lipoproteins, intermediate-density lipoproteins, very low density lipoproteins, VLDL remnants, chylomicrons, chylomicron remnants, and lipoprotein [a]) [118]. Non-HDL cholesterol is a calculation of total cholesterol minus the cholesterol carried by HDL particles (i.e., total cholesterol – HDL cholesterol). Likely because of its inclusive nature, non-HDL cholesterol is a better predictor of ASCVD risk than LDL cholesterol. Furthermore, changes in non-HDL cholesterol with dyslipidemia treatment are more strongly associated with reduced ASCVD risk than with on-treatment LDL cholesterol levels [119]. Yet despite its primary importance regarding diagnosis and treatment of dyslipidemia, non-HDL cholesterol is rarely reported in bariatric procedure clinical trials.

Similarly, an integral contributor to atherosclerosis is incorporation of atherogenic lipoproteins within the subendothelia, which promotes the inflammatory process potentially leading to ASCVD events (see Part 1 of this Scientific Statement). Given that 1 molecule of apoB resides on every atherogenic lipoprotein, apoB can be considered a surrogate for atherogenic lipoprotein particles. Diagnostically, whenever discordance exists between LDL cholesterol and either LDL particles or apoB, the latter 2 lipid parameter are superior in predicting ASCVD risk [119]. That is why apoB is sometimes considered a treatment target, with assigned treatment goals, by various interna- tional lipid guidelines [118,159,160]. Despite the central role of apoB and LDL particle numbers to atherosclerosis, these parameters are rarely reported in bariatric procedure clinical trials.

Yet another lipid parameter with scarce reporting is remnant lipoproteins. Increased triglyceride-rich lipoproteins are potentially transformed into lipoprotein remnants. Remnant particles may become incorporated into arterial subendothelia. Although remnant lipoproteins are much larger than LDL, and thus may have less potential to cross the endothelium, each remnant particle contains about 40 times more cholesterol compared with low-density lipoproteins. Thus, remnant lipoproteins are important contributors to atherosclerosis, and postprandial dyslipidemia is an important ASCVD risk factor [161,162]. Some literature supports that bariatric surgery improves both fasting and postprandial lipid levels, possibly because of impaired intestinal cholesterol absorption and improved insulin sensitivity, which might enhance postprandial clearance of triglyceride-rich lipoproteins [129,163,164]. However, given the high prevalence of hypertriglycemia in the population, the importance of remnant lipoproteins in the process of atherosclerosis, and the potential of bariatric procedures to improve clearance of triglyceride-rich lipoproteins and remnant lipoproteins, the amount of data regarding the effects of bariatric procedures on remnant lipoproteins could be more robust.

Finally, 2 other lipid parameters scarcely reported in trials of bariatric procedures include lipoprotein a (Lp[a]) and LDL particle size. Lp(a) is a lipoprotein similar to LDL and consists of an LDL molecule attached to a second protein, apo (a). Apo (a) has a structure similar to plasminogen. Although elevated Lp(a) is a risk factor for ASCVD, nutritional intervention or increased physical activity is not known to decrease its levels. Therefore, it is not surprising that on the rare instances Lp(a) was reported in bariatric procedure clinical trials, Lp(a) levels were not changed. The other lipid parameter scarcely reported is LDL particle size. Presumably, the smaller the LDL particle size (as often occurs in patients with adiposopathy, glucose intolerance, diabetes mellitus, and metabolic syndrome), the greater the potential to enter the arterial subendothelial wall. Furthermore, smaller LDL particles may have less affinity to LDL receptors, increasing their persistence in the circulation and exposure to the arterial endothelia. Smaller LDL particles are more easily oxidized upon interactions with subendothelial macrophages. However, although lipoprotein particle size may have diagnostic value, little evidence supports lipoprotein particle size as a treatment target or a clinically useful postintervention metric [119,120,165].

Bariatric procedures and atherosclerotic cardiovascular disease

Historical importance of intestinal procedures in validating the cholesterol hypothesis: Program on Surgical Control of the Hyperlipidemias (POSCH)

At least since the 1960s, intestinal surgery (i.e., ileal bypass) was employed as a way to reduce hyperlipidemia [166]. One of the first classic clinical trials to test the “cholesterol hypothesis” was the Program on Surgical Control of the Hyperlipidemias (POSCH), which was a randomized, secondary intervention trial among patients with prior myocardial infarction, evaluating the combination of nutritional intervention and partial ileal bypass (PIB) [167]. In this study of 838 participants, an interim analysis revealed that 396 (196 control and 200 surgical patients) had complete 5-year lipoprotein results [168]. Compared with control patients, the PIB group had a 24% reduction in total cholesterol and a 38% reduction in LDL cholesterol. Also compared with the control group, although triglyceride and VLDL cholesterol levels were higher, the PIB group had significantly lower apolipoprotein B-100 levels (reflecting an overall reduction of atherogenic lipoprotein particle number), as well as consistently higher HDL cholesterol and apolipoprotein A-I and HDL-2 levels. It was noted these lipoprotein changes were greater than reported from previous trials of dietary or pharmacologic intervention, which at the time included clinical trial results of bile acid resins [169]. Based on these lipoprotein effects of this intestinal surgery, the hypothesized predictive outcome was that PIB would demonstrate a reduction in ASCVD morbidity and mortality. After a mean follow-up of 9.7 years, the PIB group had a statistically significant mean weight loss of 5.3 kg (weight in the control group was not reported) [170]. Compared with the control group, PIB was found to produce sustained improvement in lipid levels, as well as a statistically significant 35% reduction in the combined endpoints of death as a result of coronary heart disease and confirmed nonfatal myocardial infarction, as well as a statistically significant reduction in coronary artery bypass grafting and reduction in angiographic atherosclerotic lesion progression. PIB also resulted in a reduction in overall mortality (estimated 149 deaths per 1000 in the control group versus 116 per 1000 in the PIB group), although this did not achieve statistical significance. Overall, this sentinel trial of an intestinal surgical procedure provided “strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression” [170].

Bariatric procedures, cardiovascular disease risk factors, cardiovascular disease outcomes, and overall mortality

Regarding cardiovascular disease risk factors, current bariatric surgical procedures for the purpose of weight loss have shown a consistent reduction in cardiovascular risk factors. Most studies of bariatric procedures report improvement in lipid levels (Table 4) [81,107,127–149], as well as improvement in glucose levels, blood pressure, endothelial function, C-reactive protein, and ASCVD risk scores, such as the Framingham risk score [60]. In a systematic review of cardiovascular risk factors [171], bariatric surgery improved hyperlipidemia in 65% of patients, as well as improved diabetes mellitus in 73% and hypertension in 63% of patients. Echocardiographic data after bariatric surgery indicated significant improvements in left ventricular mass and function [171].

Regarding cardiovascular events, in a meta-analysis of clinical trials comparing bariatric surgery versus nonsurgical treatment, bariatric surgery patients had a statistically significant reduction in myocardial infarction (odds ratio = .54), stroke (odds ratio =1 .49), and composite ASDVD events (odds ratio = .54) and a 50% reduction in overall mortality [80].

Regarding deaths, the Swedish Obese Patients (SOS) study was the first large-scale, long-term, prospective, controlled trial to report the effects of bariatric surgery on the incidence of cardiovascular disease and overall mortality, as well as diabetes mellitus and cancer [172]. The SOS study evaluated 2010 patients with obesity who underwent bariatric surgery (gastric bypass [13%], banding [19%], and vertical banded gastroplasty [68%]), and compared the health outcomes to 2037 contemporaneously matched obese control patients receiving usual care. The age of participants was 37–60 years and body mass index (BMI) was Z34 kg/m2 in men and Z38 kg/m2 in women. Follow-up periods varied from 10 to 20 years. The mean changes in weight after 2, 10, 15, and 20 years were –23%, –17%, –16%, and –18% in the surgery group and 0%, 1%, –1%, and –1% in the control group, respectively. Compared with usual care, bariatric surgery produced a reduction in overall mortality (primary endpoint) and myocardial infarction, as well as decreased diabetes mellitus, stroke, and decreased cancer in women. In a 2- and 10-year follow-up publication, LDL cholesterol, non-HDL, apolipoprotein B, and lipoprotein particle number were not reported. However, although total cholesterol did not statistically change at 10 years, bariatric surgery did produce significant decreases in triglyceride and significant increases in HDL cholesterol levels [3,173].

Postbariatric deficiencies of vitamins, minerals, and trace elements, and their potential lipid effects

The main purpose of the gastrointestinal tract is to digest foodstuffs, absorb nutrients, and expel waste. The previous section described digestion of food, which is important in understanding the potential mechanisms of action of bariatric procedures. Also relevant is an understanding of vitamin, minerals, and trace element absorption, as well as the location of nutrient absorption. Vitamins are essential organic compounds that cannot be synthesized in the body. Vitamins are derived from plant and animal foods, and necessary for metabolic processes, such as serving as a nonprotein facilitator (coenzyme) for protein enzymes. Minerals (e.g., calcium, phosphorous, magnesium, potassium, and sodium) are nonorganic substances necessary for important biological processes (e.g., vital part of an enzyme). Trace elements (e.g., iron, cobalt, zinc, selenium, molybdenum, and iodine) are nonorganic substances required by the body for biological functions (e.g., vital part of an enzyme), but only in minute amounts. Regarding location of absorption, the stomach represents the location for substantial absorption of water and alcohol. The duodenum is especially important for absorption of fatty acids, amino acids, some minerals (e.g., iron and calcium, especially during calcium deficiency). Largely because of its length and location, the jejunum absorbs the greatest amount of fatty acids, simple sugars, and amino acids, as well as most minerals (e.g., calcium) and vitamins. The ileum is a location important for absorption of bile salts and vitamin B12, as well as some vitamins and minerals. Finally, the colon absorbs some water, sodium chloride, potassium, and intestinally derived vitamin K. Bariatric procedures often involve the manipulation of the location of gastrointestinal tract nutrient absorption, which may directly affect absorbed nutrient quantity and quality; both can affect lipid blood levels.

The American Association of Clinical Endocrinologists, the Obesity Society, and the American Society for Metabolic and Bariatric Surgery have issued guidelines toward the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. This guideline includes a checklist of items to monitor (including vitamins and mineral assessments) based on the type of bariatric procedure (laparoscopic gastric banding, laproscopic sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion with duodenal switch) as well as the timing for such assessments [174]. In general, postprocedure micro- nutrient malabsorption deficiencies in vitamins, minerals, and trace elements are more common with bariatric procedures that involve intestinal resection, with relocation of intestinal connections. Thus, so-called malabsorptive procedures such as gastric bypass and biliopancreatic diversion/duodenal switch are reported to have a greater risk for postprocedure deficiencies in vitamins, minerals, and trace elements than laparoscopic adjustable gastric banding [175]. In general, although multivitamin supplementation is recommended for all bariatric procedures, laparoscopic adjustable gastric banding has among the lowest rate of postoperative micronutrient deficiency. Sleeve gastrectomy also has a low rate of postoperative micronutrient deficiency, although monitoring of selected vitamins, minerals, and trace elements are often performed. Roux-en-Y gastric bypass has a higher rate of postoperative micronutrient deficiency, and selected vitamins, minerals, and trace elements are routinely performed. Finally, biliopancreatic diversion/duodenal switch has among the highest rate of postoperative micronutrient deficiency, and selected vitamins, minerals, and trace elements are routinely performed. In the absence of signs or symptoms of deficiency, and in addition to complete blood cell count, general blood chemistries (including liver enzymes and glucose levels), and lipid profile, the vitamin, mineral, and trace element levels most commonly evaluated after bariatric surgery include thiamine, folate, vitamin B12, 25-hydroxyl-(OH)-vitamin D, parathyroid hormone, calcium, phosphorous, magnesium, iron, and ferritin, with most of these applicable in detecting potential causes of postoperative anemia. Post-operative dual-energy X-ray (DEXA) is also sometimes performed to assess bone mineral density and body composition.

Postbariatric procedure vitamin, mineral, and trace element deficiencies, and their effects on lipid levels, are described in Tables 5 [1,175–224] and 6 [1,111,175,181–184,225–244]. It is challenging to predict how bariatric procedures may affect lipid levels in patients with post-operative micronutrient malabsorption of vitamins, minerals, and trace elements from the intestine. That is because micronutrient deficiencies are often present before bariatric procedures (e.g., vitamin D), and because postoperatively, if 1 vitamin, mineral, or trace elements is deficient, then it is likely the underlying malabsorptive state is affecting other vitamins, minerals, and trace elements as well. Given that different vitamins, minerals, and trace elements may facilitate different effects on nutrient metabolism, via different effects on influx, efflux, anabolism, and catabolism, then the effect of multiple vitamin, mineral, and trace element deficiencies will likely have mixed biologic influences on determination of net lipid blood level (some deficiencies may increase lipid levels; others may decrease lipid levels). In cases of both micro and macronutrient malabsorption, diminished intestinal nutrient absorption may also substantially affect lipid blood levels. Table 7 describes replacement of select postoperative vitamin and mineraldeficiencies [1,245,246]. This may help explain why bariatric procedures may have varied postoperative effects on lipid blood levels, with lipid levels dependent on: (1) postbariatric procedure nutritional and physical activity, (2) caloric intake and other potential effects on macronutrients, (3) hormonal and metabolic effects of bariatric surgery, and (4) the degree by which micronutrient deficiencies are avoided or successfully treated.

Conclusions

Bariatric procedures improve multiple cardiovascular risk factors, including glucose metabolism, blood pressure, factors related to thrombosis, kidney function, adipocyte and adipose tissue function, inflammatory markers, and vascular markers. This helps explain why bariatric procedures may reduce ASCVD risk. Bariatric procedures also improve lipid levels, which is another potential contributor to reduced ASCVD risk. Principles that apply to bariatric procedures and lipid levels include the following: (1) The greater the fat mass loss, the greater the improvement in lipid parameters such as triglycerides and especially LDL cholesterol; (2) bariatric procedures allow for a decrease in the use of drug treatment for dyslipidemia; and (3) after bariatric procedures, HDL cholesterol may transiently decrease for the first 3–6 months after the procedure, which is usually followed by an increase in HDL cholesterol above the baseline value before the bariatric procedure. Finally, data are scarce regarding the effects of bariatric procedures on some of the lipid parameters of most interest to lipidologists, such as non-HDL cholesterol, apolipoprotein B, and lipoprotein particle number and remnant lipoproteins.

Disclosures

Harold Bays, M.D., is not a bariatric surgeon and has no industry disclosures regarding bariatric procedures. However, regarding other disclosures, in the past 12 months, Dr. Harold Bays’ research site has received research grants from Amarin, Amgen, Ardea, Arisaph, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Hanmi, Hisun, Hoffman LaRoche, Home Access, Janssen, Johnson and Johnson, Merck, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, and TIMI. In the past 12 months, Dr. Harold Bays has served as a consultant and/or speaker to Alnylam, Amarin, Amgen, Astra Zeneca, Eisai, Eli Lilly, Merck, Novartis, NovoNordisk, Regeneron, Sanofi and Takeda.

Peter Jones, M.D., reports being a consultant and scientific advisor to Merck, Amgen, Sanofi/Regeneron, and Chief Scientific Officer for the National Lipid Association.

Terry A. Jacobsen reports no disclosures.

David E. Cohen, M.D., Ph.D. is not a bariatric surgeon and has no industry disclosures regarding bariatric procedures. However, regarding other disclosures, in the ast 12 months, Dr. David Cohen has served as a consultant to Aegerion, Merck, Genzyme, Synageva, and Intercept.

Carl Orringer, M.D. reports no disclosures.

Shanu N. Kothari, M.D., Dan E. Azagury, M.D., John M. Morton, M.D., and Ninh Nguyen, M.D. report no disclosures.

References

[1] Bays HE, Gonzalez-Campoy JM. Adiposopathy. In: Friedberg EC, Castrillon DH, Galindo RL, Wharton K, eds. New opathies: an emerging molecular reclassification of human disease. Hackensack, NJ: World Scientific; 2012. p. 105–68.

[2] Bays H. Adiposopathy, “sick fat,” Ockham’s razor, and resolution of the obesity paradox. Curr Atheroscler Rep 2014;16(5):409.

[3] Bays HE, Toth PP, Kris-Etherton PM, et al. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J Clin Lipidol 2013;7(4):304–83.

[4] Raclot T, Holm C, Langin D. Fatty acid specificity of hormone-sensitive lipase. Implication in the selective hydrolysis of triacylglycerols. J Lipid Res 2001;42(12):2049–57.

[5] Harris K, Kassis A, Major G, Chou CJ. Is the gut microbiota a new factor contributing to obesity and its metabolic disorders? J Obes 2012;2012:879151.

[6] Seger JC, Horn DB, Westman EC, et al. Obesity algorithm, presented by the American Society of Bariatric Physicians. Version 2013–2014 [homepage on the Internet]. Denver (CO): American Society of Bariatric Physicians; c2015–2016 [cited 2014 Jan 31; accessed 2016 Feb 17]. Available from: www.obesityalgorithm.org.

[7] Bays H. Central obesity as a clinical marker of adiposopathy; increased visceral adiposity as a surrogate marker for global fat dysfunction. Curr Opin Endocrinol Diabetes Obes 2014;21 (5):345–51.

[8] Eckel RH, Jakicic JM, Ard JD, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2960–84.

[9] American Association of Clinical Endocrinologists/the American College of Endocrinology, Obesity Society, Gonzalez-Campoy JM, et al. Clinical practice guidelines for healthy eating for the prevention and treatment of metabolic and endocrine diseases in adults: cosponsored by the American Association of Clinical Endocrinologists/the American College of Endocrinology and the Obesity Society: executive summary. Endocr Pract 2013;19 (5):875–87.

[10] Stein J, Stier C, Raab H, Weiner R. Review article: the nutritional and pharmacological consequences of obesity surgery. Aliment Pharmacol Ther 2014;40(6):582–609.

[11] Bays HE. Adiposopathy, diabetes mellitus, and primary prevention of atherosclerotic coronary artery disease: treating “sick fat” through improving fat function with antidiabetes therapies. Am J Cardiol 2012;110(9 Suppl):4B–12B.

[12] Chaudhri O, Small C, Bloom S. Gastrointestinal hormones regulating appetite. Philos Trans R Soc Lond B Biol Sci 2006;361 (1471):1187–209.

[13] Barja-Fernandez S, Folgueira C, Castelao C, Leis R, Casanueva FF, Seoane LM. Peripheral signals mediate the beneficial effects of gastric surgery in obesity. Gastroenterol Res Pract 2015;2015: 560938.

[14] Zhang SR, Fan XM. Ghrelin-ghrelin Oacyltransferase system in the pathogenesis of nonalcoholic fatty liver disease. World J Gastro-enterol 2015;21(11):3214–22.

[15] Jacobsen SH, Olesen SC, Dirksen C, et al. Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obes Surg 2012;22(7):1084–96.

[16] Peterli R, Wölnerhanssen B, Peters T, et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial. Ann Surg 2009;250(2):234–41.

[17] Tesauro M, Schinzari F, Caramanti M, Lauro R, Cardillo C. Metabolic and cardiovascular effects of ghrelin. Int J Pept 2010;2010: pii: 864342.

[18] Magnusson I, Einarsson K, Angelin B, Nyberg B, Bergström K, Thulin L. Effects of somatostatin on hepatic bile formation. Gastroenterology 1989;96(1):206–12.

[19] Falkén Y, Hellström PM, Holst JJ, Näslund E. Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab 2011;96(7):2227–35.

[20] Cho YM. A gut feeling to cure diabetes: potential mechanisms of diabetes remission after bariatric surgery. Diabetes Metab J 2014;38 (6):406–15.

[21] Woods SC, Lutz TA, Geary N, Langhans W. Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos Trans R Soc Lond B Biol Sci 2006;361(1471):1219–35.

[22] Rodgers RL. Glucagon and cyclic AMP: time to turn the page? Curr Diabetes Rev 2012;8(5):362–81.

[23] Campos GM, Rabl C, Havel PJ, et al. Changes in post-prandial glucose and pancreatic hormones, and steady-state insulin and free fatty acids after gastric bypass surgery. Surg Obes Relat Dis 2014;10 (1):1–8.

[24] Parmley WW, Glick G, Sonnenblick EH. Cardiovascular effects of glucagon in man. N Engl J Med 1968;279(1):12–7.

[25] le Roux CW, Aylwin SJ, Batterham RL, et al. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 2006;243 (1):108–14.

[26] Schrumpf E, Linnestad P, Nygaard K, Giercksky KE, Fausa O. Pancreatic polypeptide secretion before and after gastric bypass surgery for morbid obesity. Scand J Gastroenterol 1981;16 (8):1009–14.

[27] Nannipieri M, Baldi S, Mari A, et al. Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. J Clin Endocrinol Metab 2013;98(11):4391–9.

[28] Yang F. Amylin in vasodilation, energy expenditure and inflammation. Front Biosci (Landmark Ed) 2014;19:936–44. [29] Bose M, Machineni S, Oliván B, et al. Superior appetite hormone profile after equivalent weight loss by gastric bypass compared to gastric banding. Obesity (Silver Spring) 2010;18(6):1085–91.

[30] Porchia LM, Torres-Rasgado E, Elba Gonzalez-Mejia M, et al. Serum amylin indicates hypertriglyceridemia in prediabetics. J. Diabetes Metab 2015;6:509.

[31] Zhou L, Yang H, Lin X, Okoro EU, Guo Z. Cholecystokinin elevates mouse plasma lipids. PLoS One 2012;7(12):e51011.

[32] Sekar R, Chow BK. Lipolytic actions of secretin in mouse adipocytes. J Lipid Res 2014;55(2):190–200.

[33] Rubino F, Gagner M, Gentileschi P, et al. The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg 2004;240(2):236–42.

[34] Whitson BA, Leslie DB, Kellogg TA, et al. Entero-endocrine changes after gastric bypass in diabetic and nondiabetic patients: a preliminary study. J Surg Res 2007;141(1):31–9.

[35] Cuomo R, Vandaele P, Coulie B, et al. Influence of motilin on gastric fundus tone and on meal-induced satiety in man: role of cholinergic pathways. Am J Gastroenterol 2006;101(4):804–11.

[36] Sanger GJ. Ghrelin and motilin receptor agonists: a long and winding misconception. Neurogastroenterol Motil 2013;25 (12):1002.

[37] Näslund E, Grybäck P, Hellström PM, et al. Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. Int J Obes Relat Metab Disord 1997;21 (5):387–92.

[38] Miegueu P, Cianflone K, Richard D, St-Pierre DH. Motilin stimulates preadipocyte proliferation and differentiation and adipocyte lipid storage. Am J Physiol Endocrinol Metab 2011;301 (5):E758–66.

[39] Zhang J, Li HT, Fang QC, Jia WP. Role of fibroblast growth factor 19 in maintaining nutrient homeostasis and disease. Biomed Environ Sci 2014;27(5):319–24.

[40] Ryan KK, Kohli R, Gutierrez-Aguilar R, Gaitonde SG, Woods SC, Seeley RJ. Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 2013;154(1):9–15.

[41] Pournaras DJ, Glicksman C, Vincent RP, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology 2012;153(8):3613–9.

[42] Sun F, Wu S, Wang J, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther 2015;37: 225–41.e8.

[43] Jeppesen PB. Pharmacologic options for intestinal rehabilitation in patients with short bowel syndrome. JPEN J Parenter Enteral Nutr 2014;38(1 Suppl):45S–52S.

[44] le Roux CW, Borg C, Wallis K, et al. Gut hypertrophy after gastric bypass is associated with increased glucagon-like peptide 2 and intestinal crypt cell proliferation. Ann Surg 2010;252(1):50–6.

[45] Dash S, Xiao C, Morgantini C, Connelly PW, Patterson BW, Lewis GF. Glucagon-like peptide-2 regulates release of chylomicrons from the intestine. Gastroenterology 2014;147(6):1275–1284.e4.

[46] Laferrère B, Swerdlow N, Bawa B, et al. Rise of oxyntomodulin in response to oral glucose after gastric bypass surgery in patients with type 2 diabetes. J Clin Endocrinol Metab 2010;95(8):4072–6.

[47] Kerr BD, Flatt PR, Gault VA. (D-Ser2)Oxm[mPEG-PAL]: a novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions. Biochem Pharmacol 2010;80(11):1727–35.

[48] Grenier E, Garofalo C, Delvin E, Levy E. Modulatory role of PYY in transport and metabolism of cholesterol in intestinal epithelial cells. PLoS One 2012;7(7):e40992.

[49] Bays HE, Neff D, Tomassini JE, Tershakovec AM. Ezetimibe: cholesterol lowering and beyond. Expert Rev Cardiovasc Ther 2008;6(4):447–70.

[50] Chandrasekharan B, Nezami BG, Srinivasan S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am J Physiol Gastrointest Liver Physiol 2013;304(11):G949–57.

[51] Holzer P, Farzi A. Neuropeptides and the microbiota-gut-brain axis. Adv Exp Med Biol 2014;817:195–219.

[52] Rudnicki M, McFadden DW, Sheriff S, Fischer JE. Roux-en-Y jejunal bypass abolishes postprandial neuropeptide Y release. J Surg Res 1992;53(1):7–11.

[53] Rojas JM, Bruinstroop E, Printz RL, et al. Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation. Mol Metab 2015;4(3):210–21.

[54] Zámbó V, Simon-Szabó L, Szelényi P, Kereszturi E, Bánhegyi G, Csala M. Lipotoxicity in the liver. World J Hepatol 2013;5 (10):550–7.

[55] Rossmeisl M, Medrikova D, van Schothorst EM, et al. Omega-3 phospholipids from fish suppress hepatic steatosis by integrated inhibition of biosynthetic pathways in dietary obese mice. Biochim Biophys Acta 2014;1841(2):267–78.

[56] Bays H. From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus. Curr Med Res Opin 2009;25 (3):671–81.

[57] Rippe JM. The metabolic and endocrine response and health implications of consuming sugar-sweetened beverages: findings from recent randomized controlled trials. Adv Nutr 2013;4 (6):677–86.

[58] Akram M, Hamid A. Mini review on fructose metabolism. Obes Res Clin Pract 2013;7(2):e89–e94.

[59] Mackey RH, Belle SH, Courcoulas AP, et al. Longitudinal Assessment of Bariatric Surgery Consortium Writing Group. Distribution of 10-year and lifetime predicted risk for cardiovascular disease prior to surgery in the longitudinal assessment of bariatric surgery-2 study. Am J Cardiol 2012;110(8):1130–7.

[60] Heneghan HM, Meron-Eldar S, Brethauer SA, Schauer PR, Young JB. Effect of bariatric surgery on cardiovascular risk profile. Am J Cardiol 2011;108(10):1499–507.

[61] Bays HE. Adiposopathy is “sick fat” a cardiovascular disease? J Am Coll Cardiol 2011;57(25):2461–73.

[62] Yu J, Zhou X, Li L, et al. The long-term effects of bariatric surgery for type 2 diabetes: systematic review and meta-analysis of randomized and non-randomized evidence. Obes Surg 2015;25 (1):143–58.

[63] Puzziferri N, Roshek TB 3rd, Mayo HG, Gallagher R, Belle SH, Livingston EH. Long-term follow-up after bariatric surgery: a systematic review. JAMA 2014;312(9):934–42.

[64] Nguyen KT, Korner J. The sum of many parts: potential mechanisms for improvement in glucose homeostasis after bariatric surgery. Curr Diab Rep 2014;14(5):481.

[65] Maleckas A, Venclauskas L, Wallenius V, Lonroth H, Fandriks L. Surgery in the treatment of type 2 diabetes mellitus. Scand J Surg 2015;104(1):40–7.

[66] Abbatini F, Capoccia D, Casella G, Soricelli E, Leonetti F, Basso N. Long-term remission of type 2 diabetes in morbidly obese patients after sleeve gastrectomy. Surg Obes Relat Dis 2013;9(4):498–502.

[67] Brethauer SA, Aminian A, Romero-Talamas H, et al. Can diabetes be surgically cured? Long-term metabolic effects of bariatric surgery in obese patients with type 2 diabetes mellitus. Ann Surg 2013;258 (4):628–36.

[68] Adams TD, Davidson LE, Litwin SE, et al. Health benefits of gastric bypass surgery after 6 years. JAMA 2012;308(11):1122–31.

[69] Adams ST, Salhab M, Hussain ZI, Miller GV, Leveson SH. Obesity-related hypertension and its remission following gastric bypass surgery—a review of the mechanisms and predictive factors. Blood Press 2013;22(3):131–7.

[70] Aghamohammadzadeh R, Greenstein AS, Yadav R, et al. Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. J Am Coll Cardiol 2013;62(2):128–35.

[71] Ahmed AR, Rickards G, Coniglio D, et al. Laparoscopic Roux-en-Y gastric bypass and its early effect on blood pressure. Obes Surg 2009;19(7):845–9.

[72] Bueter M, Ahmed A, Ashrafian H, le Roux CW. Bariatric surgery and hypertension. Surg Obes Relat Dis 2009;5(5):615–20.

[73] Fenske WK, Dubb S, Bueter M, et al. Effect of bariatric surgery-induced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study. Surg Obes Relat Dis 2013;9 (4):559–68.

[74] Sarkhosh K, Birch DW, Shi X, Gill RS, Karmali S. The impact of sleeve gastrectomy on hypertension: a systematic review. Obes Surg 2012;22(5):832–7.

[75] Wilhelm SM, Young J, Kale-Pradhan PB. Effect of bariatric surgery on hypertension: a meta-analysis. Ann Pharmacother 2014;48 (6):674–82.

[76] Fernstrom JD, Courcoulas AP, Houck PR, Fernstrom MH. Long-term changes in blood pressure in extremely obese patients who have undergone bariatric surgery. Arch Surg 2006;141(3):276–83.

[77] Flores L, Vidal J, Canivell S, Delgado S, Lacy A, Esmatjes E. Hypertension remission 1 year after bariatric surgery: predictive factors. Surg Obes Relat Dis 2014;10(4):661–5.

[78] Wiewiora M, Piecuch J, Glück M, Slowinska-Lozynska L, Sosada K. Impact of sleeve gastrectomy on red blood cell aggregation: a 12- month follow-up study. Int J Obes (Lond) 2014;38(10):1350–6.

[79] Pardina E, Ferrer R, Rivero J, et al. Alterations in the common pathway of coagulation during weight loss induced by gastric bypass in severely obese patients. Obesity (Silver Spring) 2012;20 (5):1048–56.

[80] Kwok CS, Pradhan A, Khan MA, et al. Bariatric surgery and its impact on cardiovascular disease and mortality: a systematic review and meta-analysis. Int J Cardiol 2014;173(1):20–8.

[81] Woodard GA, Peraza J, Bravo S, Toplosky L, Hernandez-Boussard T, Morton JM. One year improvements in cardiovascular risk factors: a comparative trial of laparoscopic Roux-en-Y gastric bypass vs. adjustable gastric banding. Obes Surg 2010;20 (5):578–82.

[82] Sledzinski T, Goyke E, Smolenski RT, Sledzinski Z, Swierczynski J. Decrease in serum protein carbonyl groups concentration and maintained hyperhomocysteinemia in patients undergoing bariatric surgery. Obes Surg 2009;19(3):321–6.

[83] Netto BD, Bettini SC, Clemente AP, et al. Roux-en-Y gastric bypass decreases pro-inflammatory and thrombotic biomarkers in individuals with extreme obesity. Obes Surg 2015;25(6):1010–8.

[84] Bolignano D, Zoccali C. Effects of weight loss on renal function in obese CKD patients: a systematic review. Nephrol Dial Transplant 2013;28(Suppl 4):iv82–98.

[85] Agrawal V, Krause KR, Chengelis DL, Zalesin KC, Rocher LL, McCullough PA. Relation between degree of weight loss after bariatric surgery and reduction in albuminuria and C-reactive protein. Surg Obes Relat Dis 2009;5(1):20–6.

[86] Amor A, Jiménez A, Moizé V, et al. Weight loss independently predicts urinary albumin excretion normalization in morbidly obese type 2 diabetic patients undergoing bariatric surgery. Surg Endosc 2013;27(6):2046–51.

[87] Mohan S, Tan J, Gorantla S, Ahmed L, Park CM. Early improvement in albuminuria in non-diabetic patients after Roux-en-Y bariatric surgery. Obes Surg 2012;22(3):375–80.

[88] Navaneethan SD, Kelly KR, Sabbagh F, Schauer PR, Kirwan JP, Kashyap SR. Urinary albumin excretion, HMW adiponectin, and insulin sensitivity in type 2 diabetic patients undergoing bariatric surgery. Obes Surg 2010;20(3):308–15.

[89] Oberbach A, Neuhaus J, Inge T, et al. Bariatric surgery in severely obese adolescents improves major comorbidities including hyperuricemia. Metabolism 2014;63(2):242–9.

[90] Panunzi S, De Gaetano A, Carnicelli A, Mingrone G. Predictors of remission of diabetes mellitus in severely obese individuals undergoing bariatric surgery: do BMI or procedure choice matter? A meta- analysis. Ann Surg 2015;261(3):459–67.

[91] Pontiroli AE, Pizzocri P, Giacomelli M, et al. Ultrasound measurement of visceral and subcutaneous fat in morbidly obese patients before and after laparoscopic adjustable gastric banding: comparison with computerized tomography and with anthropometric measurements. Obes Surg 2002;12(5):648–51.

[92] Gloy VL, Briel M, Bhatt DL, et al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. BMJ 2013;347:f5934.

[93] Appachi S, Kashyap SR. ‘Adiposopathy’ and cardiovascular disease: the benefits of bariatric surgery. Curr Opin Cardiol 2013;28 (5):540–6.

[94] Brethauer SA, Heneghan HM, Eldar S, et al. Early effects of gastric bypass on endothelial function, inflammation, and cardiovascular risk in obese patients. Surg Endosc 2011;25(8):2650–9.

[95] Woelnerhanssen B, Peterli R, Steinert RE, Peters T, Borbély Y, Beglinger C. Effects of postbariatric surgery weight loss on adipokines and metabolic parameters: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy—a prospective randomized trial. Surg Obes Relat Dis 2011;7(5):561–8.

[96] Illán-Gómez F, Gonzálvez-Ortega M, Orea-Soler I, et al. Obesity and inflammation: change in adiponectin, C-reactive protein, tumour necrosis factor-alpha and interleukin-6 after bariatric surgery. Obes Surg 2012;22(6):950–5.

[97] Cottam DR, Mattar SG, Barinas-Mitchell E, et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg 2004;14 (5):589–600.

[98] Chen SB, Lee YC, Ser KH, et al. Serum C-reactive protein and white blood cell count in morbidly obese surgical patients. Obes Surg 2009;19(4):461–6.

[99] Gumbau V, Bruna M, Canelles E, et al. A prospective study on inflammatory parameters in obese patients after sleeve gastrectomy. Obes Surg 2014;24(6):903–8.

[100] Mallipedhi A, Prior SL, Barry JD, Caplin S, Baxter JN, Stephens JW. Changes in inflammatory markers after sleeve gastrectomy in patients with impaired glucose homeostasis and type 2 diabetes. Surg Obes Relat Dis 2014;10(6):1123–8.

[101] Habib P, Scrocco JD, Terek M, Vanek V, Mikolich JR. Effects of bariatric surgery on inflammatory, functional and structural markers of coronary atherosclerosis. Am J Cardiol 2009;104(9):1251–5.

[102] Hakeam HA, O’Regan PJ, Salem AM, Bamehriz FY, Jomaa LF. Inhibition of C-reactive protein in morbidly obese patients after laparoscopic sleeve gastrectomy. Obes Surg 2009;19(4):456–60.

[103] Miller GD, Nicklas BJ, Fernandez A. Serial changes in inflammatory biomarkers after Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis 2011;7(5):618–24.

[104] Auguet T, Terra X, Hernández M, et al. Clinical and adipocytokine changes after bariatric surgery in morbidly obese women. Obesity (Silver Spring) 2014;22(1):188–94.

[105] Viana EC, Araujo-Dasilio KL, Miguel GP, et al. Gastric bypass and sleeve gastrectomy: the same impact on IL-6 and TNF-alpha. Prospective clinical trial. Obes Surg 2013;23(8):1252–61.

[106] Pardina E, Ferrer R, Baena-Fustegueras JA, et al. Only C-reactive protein, but not TNF-alpha or IL6, reflects the improvement in inflammation after bariatric surgery. Obes Surg 2012;22(1):131–9.

[107] Julve J, Pardina E, Pérez-Cuéllar M, et al. Bariatric surgery in morbidly obese patients improves the atherogenic qualitative properties of the plasma lipoproteins. Atherosclerosis 2014;234(1):200–5.

[108] Hanusch-Enserer U, Zorn G, Wojta J, et al. Non-conventional markers of atherosclerosis before and after gastric banding surgery. Eur Heart J 2009;30(12):1516–24.

[109] João Cabrera E, Valezi AC, Delfino VD, Lavado EL, Barbosa DS. Reduction in plasma levels of inflammatory and oxidative stress indicators after Roux-en-Y gastric bypass. Obes Surg 2010;20 (1):42–9.

[110] Bower G, Toma T, Harling L, et al. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg 2015;25(12):2280–9.

[111] Priester T, Ault TG, Davidson L, et al. Coronary calcium scores 6 years after bariatric surgery. Obes Surg 2015;25(1):90–6.

[112] Tschoner A, Sturm W, Gelsinger C, et al. Long-term effects of weight loss after bariatric surgery on functional and structural markers of atherosclerosis. Obesity (Silver Spring) 2013;21 (10):1960–5.

[113] Flores L, Núñez I, Vidal J, et al. Endothelial function in hypertensive obese patients: 1 year after surgically induced weight loss. Obes Surg 2014;24(9):1581–4.

[114] Vázquez LA, Pazos F, Berrazueta JR, et al. Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery. J Clin Endocrinol Metab 2005;90(1):316–22.

[115] Saleh MH, Bertolami MC, Assef JE, et al. Improvement of atherosclerotic markers in non-diabetic patients after bariatric surgery. Obes Surg 2012;22(11):1701–7.

[116] Sturm W, Tschoner A, Engl J, et al. Effect of bariatric surgery on both functional and structural measures of premature atherosclerosis. Eur Heart J 2009;30(16):2038–43.

[117] Petersen KS, Blanch N, Keogh JB, Clifton PM. Effect of weight loss on pulse wave velocity: systematic review and meta-analysis. Arterioscler Thromb Vasc Biol 2015;35(1):243–52.

[118] Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1—executive summary. J Clin Lipidol 2014;8(5):473–88.

[119] Bays HE, Jones PH, Brown WV, Jacobson TA, National Lipid Association. National Lipid Association annual summary of clinical lipidology 2015. J Clin Lipidol 2014;8(6 Suppl):S1–36.

[120] Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol 2011;5 (5):338–67.

[121] Sniderman AD, Islam S, Yusuf S, McQueen MJ. Is the superiority of apoB over non-HDL-C as a marker of cardiovascular risk in the INTERHEART study due to confounding by related variables? J Clin Lipidol 2013;7(6):626–31.

[122] Bays HE, Laferrère B, Dixon J, et al. Adiposopathy and Bariatric Surgery Working Group. Adiposopathy and bariatric surgery: is ‘sick fat’ a surgical disease? Int J Clin Pract 2009;63(9):1285–300.

[123] Lee WJ, Chen CY, Chong K, Lee YC, Chen SC, Lee SD. Changes in postprandial gut hormones after metabolic surgery: a comparison of gastric bypass and sleeve gastrectomy. Surg Obes Relat Dis 2011;7(6):683–90.

[124] Fried M. Bariatric and metabolic surgery. Minerva Endocrinol 2013;38(3):237–44.

[125] Colquitt JL, Pickett K, Loveman E, Frampton GK. Surgery for weight loss in adults. Cochrane Database Syst Rev 2014;8: CD003641.

[126] Yip S, Plank LD, Murphy R. Gastric bypass and sleeve gastrectomy for type 2 diabetes: a systematic review and meta-analysis of outcomes. Obes Surg 2013;23(12):1994–2003. [127] Nguyen NT, Varela E, Sabio A, Tran CL, Stamos M, Wilson SE. Resolution of hyperlipidemia after laparoscopic Roux-en-Y gastric bypass. J Am Coll Surg 2006;203(1):24–9.

[128] Asztalos BF, Swarbrick MM, Schaefer EJ, et al. Effects of weight loss, induced by gastric bypass surgery, on HDL remodeling in obese women. J Lipid Res 2010;51(8):2405–12.

[129] Waldmann E, Hüttl TP, Göke B, Lang R, Parhofer KG. Effect of sleeve gastrectomy on postprandial lipoprotein metabolism in morbidly obese patients. Lipids Health Dis 2013;12:82.

[130] Nguyen NQ, Game P, Bessell J, et al. Outcomes of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding. World J Gastroenterol 2013;19(36):6035–43.

[131] Benetti A, Del Puppo M, Crosignani A, et al. Cholesterol metabolism after bariatric surgery in grade 3 obesity: differences between malabsorptive and restrictive procedures. Diabetes Care 2013;36(6):1443–7.

[132] Carroll JF, Franks SF, Smith AB, Phelps DR. Visceral adipose tissue loss and insulin resistance 6 months after laparoscopic gastric banding surgery: a preliminary study. Obes Surg 2009;19(1):47–55.

[133] Heffron SP, Singh A, Zagzag J, et al. Laparoscopic gastric banding resolves the metabolic syndrome and improves lipid profile over five years in obese patients with body mass index 30-40 kg/m(2.). Atherosclerosis 2014;237(1):183–90.

[134] Bonner GL, Nagy AJ, Jupiter DC, Rodriguez JA, Symmonds RE Jr., Carpenter RO. A comparison of postoperative effects of bariatric surgery on medical markers of morbidity. Am J Surg 2014;208 (6):897–902.

[135] Busetto L, De Stefano F, Pigozzo S, Segato G, De Luca M, Favretti F. Long-term cardiovascular risk and coronary events in morbidly obese patients treated with laparoscopic gastric banding. Surg Obes Relat Dis 2014;10(1):112–20.

[136] Aminian A, Zelisko A, Kirwan JP, Brethauer SA, Schauer PR. Exploring the impact of bariatric surgery on high density lipoprotein. Surg Obes Relat Dis 2015;11(1):238–47.

[137] Al Khalifa K, Al Ansari A, Alsayed AR, Violato C. The impact of sleeve gastrectomy on hyperlipidemia: a systematic review. J Obes 2013;2013:643530.

[138] Milone M, Lupoli R, Maietta P, et al. Lipid profile changes in patients undergoing bariatric surgery: a comparative study between sleeve gastrectomy and mini-gastric bypass. Int J Surg 2015;14: 28–32.

[139] Wong AT, Chan DC, Armstrong J, Watts GF. Effect of laparoscopic sleeve gastrectomy on elevated C-reactive protein and atherogenic dyslipidemia in morbidly obese patients. Clin Biochem 2011;44 (4):342–4.

[140] Padilla N, Maraninchi M, Béliard S, et al. Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism in obese, nondiabetic humans. Arterioscler Thromb Vasc Biol 2014;34 (10):2330–7.

[141] To VT, Hüttl TP, Lang R, Piotrowski K, Parhofer KG. Changes in body weight, glucose homeostasis, lipid profiles, and metabolic syndrome after restrictive bariatric surgery. Exp Clin Endocrinol Diabetes 2012;120(9):547–52.

[142] Stefater MA, Sandoval DA, Chambers AP, et al. Sleeve gastrectomy in rats improves postprandial lipid clearance by reducing intestinal triglyceride secretion. Gastroenterology 2011;141(3):939–949.e1-4.

[143] Williams DB, Hagedorn JC, Lawson EH, et al. Gastric bypass reduces biochemical cardiac risk factors. Surg Obes Relat Dis 2007;3(1):8–13.

[144] Dallal RM, Hatalski A, Trang A, Chernoff A. Longitudinal analysis of cardiovascular parameters after gastric bypass surgery. Surg Obes Relat Dis 2012;8(6):703–9.

[145] Behbehani F, Ammori BJ, New JP, Summers LK, Soran H, Syed AA. Metabolic outcomes 2 years following gastric bypass surgery in people with type 2 diabetes: an observational cohort study. QJM 2014;107(9):721–6.

[146] Raffaelli M, Guidone C, Callari C, Iaconelli A, Bellantone R, Mingrone G. Effect of gastric bypass versus diet on cardiovascular risk factors. Ann Surg 2014;259(4):694–9.

[147] Barakat HA, Carpenter JW, McLendon VD, et al. Influence of obesity, impaired glucose tolerance, and NIDDM on LDL structure and composition. Possible link between hyperinsulinemia and atherosclerosis. Diabetes 1990;39(12):1527–33.

[148] Corradini SG, Eramo A, Lubrano C, et al. Comparison of changes in lipid profile after bilio-intestinal bypass and gastric banding in patients with morbid obesity. Obes Surg 2005;15(3):367–77.

[149] García-Díaz Jde D, Lozano O, Ramos JC, Gaspar MJ, Keller J, Duce AM. Changes in lipid profile after biliopancreatic diversion. Obes Surg 2003;13(5):756–60.

[150] Jensen MD, Ryan DH, Apovian CM, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014;129(25 Suppl 2):S102–38.

[151] Frige F, Laneri M, Veronelli A, et al. Bariatric surgery in obesity: changes of glucose and lipid metabolism correlate with changes of fat mass. Nutr Metab Cardiovasc Dis 2009;19(3):198–204.

[152] Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA 2013;309(21):2240–9.

[153] Ties JS, Zlabek JA, Kallies KJ, Al-Hamadini M, Kothari SN. The effect of laparoscopic gastric bypass on dyslipidemia in severely obese patients: a 5-year follow-up analysis. Obes Surg 2014;24 (4):549–53.

[154] Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012;366(17):1567–76.

[155] Neovius M, Narbro K, Keating C, et al. Health care use during 20 years following bariatric surgery. JAMA 2012;308(11):1132–41.

[156] Pok EH, Lee WJ. Gastrointestinal metabolic surgery for the treatment of type 2 diabetes mellitus. World J Gastroenterol 2014;20 (39):14315–28.

[157] Zvintzou E, Skroubis G, Chroni A, et al. Effects of bariatric surgery on HDL structure and functionality: results from a prospective trial. J Clin Lipidol 2014;8(4):408–17.

[158] Jamal M, Wegner R, Heitshusen D, Liao J, Samuel I. Resolution of hyperlipidemia follows surgical weight loss in patients undergoing Roux-en-Y gastric bypass surgery: a 6-year analysis of data. Surg Obes Relat Dis 2011;7(4):473–9.

[159] Anderson TJ, Grégoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013;29(2):151–67.

[160] Grundy SM, Expert Dyslipidemia Panel. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia. J Clin Lipidol 2013;7(6):561–5.

[161] Borén J, Matikainen N, Adiels M, Taskinen MR. Postprandial hypertriglyceridemia as a coronary risk factor. Clin Chim Acta 2014;431:131–42.

[162] Jackson KG, Poppitt SD, Minihane AM. Postprandial lipemia and cardiovascular disease risk: Interrelationships between dietary, physiological and genetic determinants. Atherosclerosis 2012;220 (1):22–33.

[163] Griffo E, Nosso G, Lupoli R, et al. Early improvement of postprandial lipemia after bariatric surgery in obese type 2 diabetic patients. Obes Surg 2014;24(5):765–70.

[164] De Giorgi S, Campos V, Egli L, et al. Long-term effects of Roux-en-Y gastric bypass on postprandial plasma lipid and bile acids kinetics in female non diabetic subjects: a cross-sectional pilot study. Clin Nutr 2015;34(5):911–7.

[165] Bays H, Conard S, Leiter LA, et al. Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading? Lipids Health Dis 2010;9:136.

[166] Buchwald H, Moore RB, Varco RL. Ten years clinical experience with partial ileal bypass in management of the hyperlipidemias. Ann Surg 1974;180(4):384–92.

[167] Buchwald H, Moore RB, Varco RL. Maximum lipid reduction by partial ileal bypass: a test of the lipid-atherosclerosis hypothesis. Lipids 1977;12(1):53–8.

[168] Campos CT, Matts JP, Fitch LL, Speech JC, Long JM, Buchwald H. Lipoprotein modification achieved by partial ileal bypass: five-year results of The Program on the Surgical Control of the Hyperlipidemias. Surgery 1987;102(2):424–32.

[169] Bays HE, Goldberg RB. The ‘forgotten’ bile acid sequestrants: is now a good time to remember? Am J Ther 2007;14(6):567–80.

[170] Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990;323(14):946–55.

[171] Vest AR, Heneghan HM, Agarwal S, Schauer PR, Young JB. Bariatric surgery and cardiovascular outcomes: a systematic review. Heart 2012;98(24):1763–77.

[172] Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial – a prospective controlled intervention study of bariatric surgery. J Intern Med 2013;273(3):219–34.

[173] Sjöström L, Lindroos AK, Peltonen M, et al. Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351(26):2683–93.

[174] Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and non-surgical support of the bariatric surgery patient–2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis 2013;9(2):159–91.

[175] Sawaya RA, Jaffe J, Friedenberg L, Friedenberg FK. Vitamin, mineral, and drug absorption following bariatric surgery. Curr Drug Metab 2012;13(9):1345–55.

[176] Stoll D, Binnert C, Mooser V, Tappy L. Short-term administration of isotretinoin elevates plasma triglyceride concentrations without affecting insulin sensitivity in healthy humans. Metabolism 2004;53 (1):4–10.

[177] Sauvant P, Cansell M, Atgié C. Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes. J Physiol Biochem 2011;67(3):487–96.

[178] Ertam I, Alper S, Unal I. Is it necessary to have routine blood tests in patients treated with isotretinoin? J Dermatolog Treat 2006;17 (4):214–6.

[179] Relevy NZ, Harats D, Harari A, et al. Vitamin A-deficient diet accelerated atherogenesis in apolipoprotein E(-/-) mice and dietary beta-carotene prevents this consequence. Biomed Res Int 2015;2015: 758723.

[180] Landrier JF, Marcotorchino J, Tourniaire F. Lipophilic micronutrients and adipose tissue biology. Nutrients 2012;4(11):1622–49.

[181] Xanthakos SA. Nutritional deficiencies in obesity and after bariatric surgery. Pediatr Clin North Am 2009;56(5):1105–21.

[182] Aarts EO, Janssen IM, Berends FJ. The gastric sleeve: losing weight as fast as micronutrients? Obes Surg 2011;21(2):207–11.

[183] Pech N, Meyer F, Lippert H, Manger T, Stroh C. Complications and nutrient deficiencies two years after sleeve gastrectomy. BMC Surg 2012;12:13.

[184] Homan J, Betzel B, Aarts EO, et al. Vitamin and mineral deficiencies after biliopancreatic diversion and biliopancreatic diversion with duodenal switch-the rule rather than the exception. Obes Surg 2015;25(9):1626–32.

[185] Pácal L, Kuricová K, Kaňková K. Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation? World J Diabetes 2014;5 (3):288–95.

[186] Waheed P, Naveed AK, Ahmed T. Thiamine deficiency and its correlation with dyslipidaemia in diabetics with microalbuminuria. J Pak Med Assoc 2013;63(3):340–5.

[187] Thornalley PJ. The potential role of thiamine (vitamin B1) in diabetic complications. Curr Diabetes Rev 2005;1(3):287–98.

[188] Karachalias N, Babaei-Jadidi R, Kupich C, Ahmed N, Thornalley PJ. High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats. Ann N Y Acad Sci 2005;1043:777–83.

[189] Pinto JT, Cooper AJ. From cholesterogenesis to steroidogenesis: role of riboflavin and flavoenzymes in the biosynthesis of vitamin D. Adv Nutr 2014;5(2):144–63.

[190] Liao F, Huang PC. Effects of moderate riboflavin deficiency on lipid metabolism in rats. Proc Natl Sci Counc Repub China B 1987;11 (2):128–32.

[191] Manthey KC, Chew YC, Zempleni J. Riboflavin deficiency impairs oxidative folding and secretion of apolipoprotein B-100 in HepG2 cells, triggering stress response systems. J Nutr 2005;135(5):978–82.

[192] Bays HE, Ballantyne C. What’s the deal with niacin development: is laropiprant add-on therapy a winning strategy to beat a straight flush? Curr Opin Lipidol 2009;20(6):467–76.

[193] Bays HE, Rader DJ. Does nicotinic acid (niacin) lower blood pressure? Int J Clin Pract 2009;63(1):151–9.

[194] Heemskerk MM, Dharuri HK, van den Berg SA, et al. Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile. J Lipid Res 2014;55(12):2532–40.

[195] Wittwer CT, Beck S, Peterson M, Davidson R, Wilson DE, Hansen RG. Mild pantothenate deficiency in rats elevates serum triglyceride and free fatty acid levels. J Nutr 1990;120(7):719–25.

[196] Shibata K, Fukuwatari T, Higashiyama S, Sugita C, Azumano I, Onda M. Pantothenic acid refeeding diminishes the liver, perinephrical fats, and plasma fats accumulated by pantothenic acid deficiency and/or ethanol consumption. Nutrition 2013;29(5):796–801.

[197] Zhao M, Lamers Y, Ralat MA, et al. Marginal vitamin B-6 deficiency decreases plasma (n-3) and (n-6) PUFA concentrations in healthy men and women. J Nutr 2012;142(10):1791–7.

[198] Tong L. Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci 2013;70(5):863–91.

[199] Mock DM, Mock NI, Johnson SB, Holman RT. Effects of biotin deficiency on plasma and tissue fatty acid composition: evidence for abnormalities in rats. Pediatr Res 1988;24(3):396–403.

[200] Jenkins B, West JA, Koulman A. A review of odd-chain fatty acid metabolism and the role of pentadecanoic acid (c15:0) and heptadecanoic acid (c17:0) in health and disease. Molecules 2015;20 (2):2425–44.

[201] Brevik A, Veierød MB, Drevon CA, Andersen LF. Evaluation of the odd fatty acids 15:0 and 17:0 in serum and adipose tissue as markers of intake of milk and dairy fat. Eur J Clin Nutr 2005;59 (12):1417–22.

[202] Rice BH. Dairy and cardiovascular disease: a review of recent observational research. Curr Nutr Rep 2014;3:130–8.

[203] Smulders YM, Blom HJ. The homocysteine controversy. J Inherit Metab Dis 2011;34(1):93–9.

[204] Werstuck GH, Lentz SR, Dayal S, et al. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 2001;107 (10):1263–73.

[205] Pastore A, Alisi A, di Giovamberardino G, et al. Plasma levels of homocysteine and cysteine increased in pediatric NAFLD and strongly correlated with severity of liver damage. Int J Mol Sci 2014;15(11):21202–14.

[206] Kennedy DG, Kennedy S, Blanchflower WJ, et al. Cobalt-vitamin B12 deficiency causes accumulation of odd-numbered, branched-chain fatty acids in the tissues of sheep. Br J Nutr 1994;71(1):67–76.

[207] Adaikalakoteswari A, Finer S, Voyias PD, et al. Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting sadenosylmethionine and modulating the methylation of SREBF1 and LDLR genes. Clin Epigenetics 2015;7(1):14.

[208] Kumar KA, Lalitha A, Pavithra D, et al. Maternal dietary folate and/or vitamin B12 restrictions alter body composition (adiposity) and lipid metabolism in Wistar rat offspring. J Nutr Biochem 2013;24 (1):25–31.

[209] Pinchuk I, Shoval H, Dotan Y, Lichtenberg D. Evaluation of antioxidants: scope, limitations and relevance of assays. Chem Phys Lipids 2012;165(6):638–47.

[210] Cherubini A, Vigna GB, Zuliani G, Ruggiero C, Senin U, Fellin R. Role of antioxidants in atherosclerosis: epidemiological and clinical update. Curr Pharm Des 2005;11(16):2017–32.

[211] Uchida K, Nomura Y, Takase H, et al. Effect of vitamin C depletion on serum cholesterol and lipoprotein levels in ODS (od/od) rats unable to synthesize ascorbic acid. J Nutr 1990;120(10):1140–7.

[212] Turley SD, West CE, Horton BJ. The role of ascorbic acid in the regulation of cholesterol metabolism and in the pathogenesis of artherosclerosis. Atherosclerosis 1976;24(1–2):1–18.

[213] Nakata Y, Maeda N. Vulnerable atherosclerotic plaque morphology in apolipoprotein E-deficient mice unable to make ascorbic acid. Circulation 2002;105(12):1485–90.

[214] Kelishadi R, Farajzadegan Z, Bahreynian M. Association between vitamin D status and lipid profile in children and adolescents: a systematic review and meta-analysis. Int J Food Sci Nutr 2014;65 (4):404–10.

[215] Jorde R, Grimnes G. Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids. Prog Lipid Res 2011;50(4):303–12.

[216] Michalska-Kasiczak M, Sahebkar A, Mikhailidis DP, et al. Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Analysis of vitamin D levels in patients with and without statin-associated myalgia—a systematic review and meta-analysis of 7 studies with 2420 patients. Int J Cardiol 2015;178:111–6.

[217] Khayznikov M, Hemachrandra K, Pandit R, Kumar A, Wang P, Glueck CJ. Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation. N Am J Med Sci 2015;7(3):86–93.

[218] Wallert M, Schmolz L, Galli F, Birringer M, Lorkowski S. Regulatory metabolites of vitamin E and their putative relevance for atherogenesis. Redox Biol 2014;2:495–503.

[219] Ricciarelli R, Zingg JM, Azzi A. Vitamin E reduces the uptake of oxidized LDL by inhibiting CD36 scavenger receptor expression in cultured aortic smooth muscle cells. Circulation 2000;102(1):82–7.

[220] Devaraj S, Hugou I, Jialal I. Alpha-tocopherol decreases CD36 expression in human monocyte-derived macrophages. J Lipid Res 2001;42(4):521–7.

[221] Suarna C, Wu BJ, Choy K, et al. Protective effect of vitamin E supplements on experimental atherosclerosis is modest and depends on preexisting vitamin E deficiency. Free Radic Biol Med 2006;41 (5):722–30.

[222] Erkkilä AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008;19(1):39–42.

[223] Vermeer C. Vitamin K: the effect on health beyond coagulation—an overview. Food Nutr Res 2012;56.

[224] Schurgers LJ, Joosen IA, Laufer EM, et al. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PLoS One 2012;7(8):e43229.

[225] Rojas-Marcos PM, Rubio MA, Kreskshi WI, Cabrerizo L, Sanchez-Pernaute A. Severe hypocalcemia following total thyroidectomy after biliopancreatic diversion. Obes Surg 2005;15(3):431–4.

[226] Hsu HH, Culley NC. Effects of dietary calcium on atherosclerosis, aortic calcification, and icterus in rabbits fed a supplemental cholesterol diet. Lipids Health Dis 2006;5:16.

[227] Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Cathe- ter Cardiovasc Interv 2014;83(6):E212–20.

[228] Jin J, Robinson AV, Hallowell PT, Jasper JJ, Stellato TA, Wilhem SM. Increases in parathyroid hormone (PTH) after gastric bypass surgery appear to be of a secondary nature. Surgery 2007;142 (6):914–20.

[229] Pugnale N, Giusti V, Suter M, et al. Bone metabolism and risk of secondary hyperparathyroidism 12 months after gastric banding in obese pre-menopausal women. Int J Obes Relat Metab Disord 2003; 27(1):110–6.

[230] Shi H, Dirienzo D, Zemel MB. Effects of dietary calcium on adipocyte lipid metabolism and body weight regulation in energy-restricted aP2-agouti transgenic mice. FASEB J 2001;15(2):291–3.

[231] Papamargaritis D, Aasheim ET, Sampson B, le Roux CW. Copper, selenium and zinc levels after bariatric surgery in patients recommended to take multivitamin-mineral supplementation. J Trace Elem Med Biol 2015;31:167–72.

[232] Kaya A, Altiner A, Ozpinar A. Effect of copper deficiency on blood lipid profile and haematological parameters in broilers. J Vet Med A Physiol Pathol Clin Med 2006;53(8):399–404.

[233] Lamb DJ, Avades TY, Ferns GA. Biphasic modulation of athero-sclerosis induced by graded dietary copper supplementation in the cholesterol-fed rabbit. Int J Exp Pathol 2001;82(5):287–94.

[234] Hamilton IM, Gilmore WS, Strain JJ. Marginal copper deficiency and atherosclerosis. Biol Trace Elem Res 2000;78(1–3):179–89.

[235] Lefevre M, Keen CL, Lonnerdal B, Hurley LS, Schneeman BO. Copper deficiency-induced hypercholesterolemia: effects on HDL subfractions and hepatic lipoprotein receptor activity in the rat. J Nutr 1986;116(9):1735–46.

[236] Huster D, Lutsenko S. Wilson disease: not just a copper disorder. Analysis of a Wilson disease model demonstrates the link between copper and lipid metabolism. Mol Biosyst 2007;3(12):816–24.

[237] Verma U, Shankar N, Madhu SV, Tandon OP, Madan N, Verma N. Relationship between iron deficiency anaemia and serum lipid levels in Indian adults. J Indian Med Assoc 2010;108(9):555–8.

[238] Meroño T, Sorroche P, Gomez Rosso LA, et al. Proatherogenic disturbances in lipoprotein profile, associated enzymes and transfer proteins in women with iron deficiency anaemia. Clin Biochem 2010;43(4–5):416–23.

[239] Tosco A, Fontanella B, Danise R, et al. Molecular bases of copper and iron deficiency-associated dyslipidemia: a microarray analysis of the rat intestinal transcriptome. Genes Nutr 2010;5(1):1–8.

[240] Dhingra S, Bansal MP. Attenuation of LDL receptor gene expression by selenium deficiency during hypercholesterolemia. Mol Cell Biochem 2006;282(1–2):75–82.

[241] Rosenblat M, Aviram M. Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies. Free Radic Biol Med 1998;24(2):305–17.

[242] Cunnane SC. Role of zinc in lipid and fatty acid metabolism and in membranes. Prog Food Nutr Sci 1988;12(2):151–88.

[243] Foster M, Petocz P, Samman S. Effects of zinc on plasma lipoprotein cholesterol concentrations in humans: a meta-analysis of randomised controlled trials. Atherosclerosis 2010;210 (2):344–52.

[244] Khoja SM, Marzouki ZM, Ashry KM, Hamdi SA. Effect of dietary zinc deficiency on rat lipid concentrations. Saudi Med J 2002;23 (1):82–6.

[245] Aills L, Blankenship J, Buffington C, Furtado M, Parrott J, Allied Health Sciences Section Ad Hoc Nutrition C. ASMBS Allied Health Nutritional Guidelines for the Surgical Weight Loss Patient. Surg Obes Relat Dis 2008;4(5 Suppl):S73–108.

[246] Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc 2010;85(8):752–7.