Impact of bariatric surgery on apolipoprotein C-III levels and lipoprotein distribution in obese human subjects

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Original Contribution

Impact of bariatric surgery on apolipoprotein C-III levels and lipoprotein distribution in obese human subjects
ge Padilla1, Sophie Beliard, Bruno Berthet, Marie Maraninchi1, Nade Juan-Patricio Nogueira, Jeanine Dupont-Roussel, Julien Mancini, Audrey Begu-Le Corroller, No emie Dubois, Rachel Grangeot, Catherine Mattei, Marion Monclar, Anastasia Calabrese, Carole Guerin, Charles Desmarchelier, Alain Nicolay, Changting Xiao, Patrick Borel, Gary F. Lewis, Rene Valero, MD, PhD* Aix–Marseille Univ, INSERM, INRA, NORT, Marseille, France (Drs Maraninchi, Padilla, Beliard, Dupont-Roussel, Desmarchelier, Nicolay, Borel, and Valero); Department of Nutrition, Metabolic Diseases, Endocrinology, CHU La Conception, APHM, Marseille, France (Drs Beliard, Begu-Le Corroller, Dubois, Grangeot, Mattei, Monclar, Calabrese, and Valero); Department of General and Endocrine Surgery, La Conception Hospital, APHM, Marseille, France (Drs Berthet and Guerin); Instituto Modelo de Gastroenterologia, Formosa, Argentina (Dr Nogueira); Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa, Argentina (Dr Nogueira); Aix–Marseille Univ, INSERM, IRD, UMR912, SESSTIM, Marseille, France (Dr Mancini); Public Health Department (BIOSTIC), Timone Hospital, APHM, Marseille, France (Dr Mancini); Laboratory of Endocrine Biochemistry, La Conception Hospital, APHM, Marseille, France (Dr Nicolay); and Department of Medicine and Physiology, Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada (Drs Xiao and Lewis) KEYWORDS: Apolipoprotein C-III; Bariatric surgery; Cardiovascular disease; Dyslipidemia; HDL; Insulin resistance; Lipoprotein metabolism; Obesity; Triglyceride-rich lipoprotein

BACKGROUND: Elevated apolipoprotein C-III (apoC-III) has been postulated to contribute to the atherogenic dyslipidemia seen in obesity and insulin-resistant states, mainly by impairing plasma triglyceride-rich lipoprotein (TRL) metabolism. Bariatric surgery is associated with improvements of several obesity-associated metabolic abnormalities, including a reduction in plasma triglycerides (TGs) and an increase in plasma high-density lipoprotein cholesterol (HDL-C). OBJECTIVES: We investigated the specific effect of bariatric surgery on apoC-III concentrations in plasma, non-HDL, and HDL fractions in relation to lipid profile parameters evolution. METHODS: A total of 132 obese subjects undergoing bariatric surgery, gastric bypass (n 5 61) or sleeve gastrectomy (n 5 71), were studied 1 month before surgery and 6 and 12 months after surgery. RESULTS: Plasma apoC-III, non-HDL-apoC-III, and HDL-apoC-III concentrations were markedly reduced after surgery and strongly associated with reduction in plasma TG. This decrease was accompanied by a redistribution of apoC-III from TRL to HDL fractions. In multivariate analysis, plasma apoC-III was the strongest predictor of TG reduction after surgery, and the increase of HDL-C was positively associated with plasma adiponectin and negatively with body mass index.

1

These authors contributed equally to this work. * Corresponding author. Service de Nutrition, Maladies metaboliques et Endocrinologie, Centre hospitalo-Universitaire de La Conception, 147 Boulevard Baille, 13005 Marseille, France.

E-mail address: [email protected] Submitted December 12, 2016. Accepted for publication February 21, 2017.

1933-2874/Ó 2017 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2017.02.012 FLA 5.4.0 DTD  JACL1075_proof  15 March 2017  5:40 pm

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CONCLUSION: Marked reduction of apoC-III and changes in its distribution between TRL and HDL consistent with a better lipid profile are achieved in obese patients after bariatric surgery. These apoCIII beneficial modifications may have implications in dyslipidemia improvement and contribute to cardiovascular risk reduction after surgery. Ó 2017 National Lipid Association. All rights reserved.

Introduction The global epidemic of obesity represents a major public health threat.1 The relationship between the severity of obesity and increased risk of mortality and morbidity has been demonstrated in several studies.2,3 Cardiovascular disease is the dominant cause of mortality and morbidity in obesity.4 Dyslipidemia is often present in obesity and represents a major cardiovascular risk factor. This typical dyslipidemia of obese, insulin-resistant individuals is characterized by a quartet of abnormalities: hypertriglyceridemia, reduction in high-density lipoprotein cholesterol (HDL-C), increase of small and dense low-density lipoprotein (LDL) and postprandial hyperlipidemia.5 The pathophysiology of this dyslipidemia is widely explained by the blood accumulation of triglyceride-rich lipoproteins (TRL) from liver (very-low-density lipoprotein [VLDL]) and intestine (chylomicrons) origin. This accumulation has been attributed to the overproduction of both VLDL6 and chylomicrons7 and to a defective TRL removal process because of a number of associated mechanisms: reduction of lipoprotein lipase (LPL) activity,8 changes in the apolipoprotein composition of TRL9 impairing particle clearance, and defect in the hepatic uptake of TRL and their remnants.8 Apolipoprotein C-III (apoC-III) is synthesized by the liver and to a lesser extent by the intestine.10 In healthy individuals, plasma apoC-III is mainly present in TRL (VLDL and chylomicrons) and HDL and is redistributed from HDL to TRL in the postprandial state.11 Indeed, rapid exchanges occur between these particles, although nonexchangeable pools of TRL-apoC-III and HDL-apoC-III have been described.12 In hypertriglyceridemic subjects, apoC-III levels proportion bound to TRL are increased in the fasting state.13 Plasma apoC-III concentration is strongly correlated with plasma triglyceride (TG) concentration14,15 and is increased in insulin-resistant states (overweight or obesity15 and type II diabetes16,17). Elevated apoC-III has been postulated to contribute to the atherogenic dyslipidemia by the impairment of TRL and HDL metabolism including increased VLDL production and secretion,18 disturbance of TRL clearance by inhibiting LPL19 or hepatic lipase,20 and interfering with TRL and their remnant binding to hepatic lipoprotein receptors.21,22 Beyond the effects of apoC-III on TRL and HDL metabolism, this apolipoprotein has also been shown to promote inflammation and endothelial cell dysfunction, potentially

contributing to atherosclerosis and cardiovascular disease.23,24 In several clinical studies, elevated apoC-III in HDL and non-HDL fractions was a significant predictor of coronary events and progression of coronary artery disease.25–28 More recently, genetic variants resulting in a loss of function and reduced apoC-III concentrations were associated with a reduction in the risk of coronary heart disease.29,30 Considering the increased mortality in obesity and the relative long-term ineffectiveness of conventional weightreducing treatments, bariatric surgery is now an accepted therapy worldwide for classes II and III of obesity. Two main procedures are performed: gastric bypass (GBP) and sleeve gastrectomy (SG). In long-term studies, bariatric surgery has been associated with a reduction of 29% in overall mortality compared with obese controls treated with conventional strategies. An important part of this decrease is due to the reduction of deaths from myocardial infarction in the surgery group.31 Reduction in several cardiovascular risk factors (hypertriglyceridemia, low HDL-C, diabetes, and hypertension) at 2 and 10 years follow-up could contribute to the improvement in the cardiovascular outcome.32 We have recently demonstrated a reduction in TRL production and an increase in particle clearance of obese subjects after bariatric surgery.33 However, the drastic improvement of dyslipidemia after bariatric surgery is not fully explained and to date, no study has been conducted to specifically investigate the effect of bariatric surgery on apoC-III. In the present study, we investigated the effect of GBP and SG on plasma apoC-III concentration, its distribution in the lipoprotein fractions, and its relation to plasma lipid profile. We hypothesized that the improvement of lipid parameters including plasma TG reduction and HDL-C increase after bariatric surgery could be associated with a reduction of plasma apoC-III concentration and a favorable change in apoC-III distribution between TRL and HDL fractions.

Materials and methods Subjects A total of 132 obese patients referred to our Nutrition Department with an indication for bariatric surgery were recruited for this study. All participants were examined

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ApoC-III reduction and redistribution after bariatric surgery

and followed by a multidisciplinary and integrated medical team consisting of an endocrinologist, a bariatric surgeon, a psychiatrist, and a dietician for at least 6 months before surgery. All the subjects met the indication criteria for bariatric surgery.34 The choice of the surgical procedure was not randomized but made by the patient and the multidisciplinary team, after a full explanation of the risks and possible benefits of each procedure. Bariatric surgery was performed by a single surgeon in the General and Endocrine Surgery Department. Sixty-one patients undergoing GBP and 71 patients undergoing SG were consecutively included. The clinical evaluation and laboratory tests were conducted at our Nutrition Department. The subjects were examined and followed by the multidisciplinary team before surgery and at least at 1, 3, 6, 9, and 12 months postsurgery with laboratory tests 1 month before and 6 and 12 months after surgery. Patients with type II diabetes met the diagnostic criteria for diabetes.35 The presurgery antidiabetic and hypolipidemic treatments of the patients are presented in Supplementary Table 1. This study was conducted in accordance with the Declaration of Helsinki, approved by the Research Ethics Board of Aix-Marseille University, and all subjects gave written informed consent.

Study design Weight, fasting biochemical parameters, body composition, and energy intake (the diet of each subject was assessed by a dietician using a self-administered food diary completed during 3 days) were measured 1 month before surgery (M0) and at 6 months (M6) and 12 months (M12) after surgery. Our study was not powered or designed to compare the effectiveness of the 2 surgical procedures, one against the other.

Laboratory methods Blood samples were collected after an overnight fast. Plasma was immediately separated by centrifugation at 2000g for 15 minutes at 4 C. Plasma TG, total cholesterol, HDL-C, and LDL-C were measured using an enzymatic colorimetric kit (cobas 6000 c 501 analyzer; Roche Diagnostics, Mannheim, Germany). Plasma glucose was assayed using the hexokinase oxidase method (cobas 6000 c 501 analyzer). Plasma insulin concentrations were determined using electrochemiluminescence method (cobas 6000 e 601 analyzer). Insulin resistance was estimated using the homeostasis model assessment as homeostasis model assessment-insulin resistance (HOMAIR) 5 fasting insulin (mUI/L) ! fasting glucose (mmol/ L)/22.5.36 HOMA-IR was not calculated for those patients with diabetes to avoid the miscalculation of HOMA-IR due to the antidiabetic drugs taken by the patients. Total apoB and apoA-I plasma concentrations were determined by immunonephelometry assay (Roche Diagnostics) using a BN ProSpec analyzer (Siemens Healthineers, Erlangen,

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Germany) and total plasma apoC-III and apoC-II levels by immunoturbidimetric assay (Kamiya Biomedical Company, Seattle, WA) using a cobas 6000 c 501 analyzer. HDL-apoC-III and HDL-apoC-II levels were measured in the supernatant after precipitation of TRL with phosphotungstic acid and magnesium chloride (bioMerieux, Marcy-l’Etoile, France). Non-HDL-apoC-III and nonHDL-apoC-II concentrations were calculated by subtracting HDL-apoC-III and HDL-apoC-II values from total plasma apoC-III and C-II measured levels. Specific enzyme-linked immunosorbent assay kit was used to measure serum levels of adiponectin (Quantikine Human Adiponectin; R&D Systems, Minneapolis, MN). Body composition was assessed using dual-energy x-ray absorptiometry method (Lunar iDXA, GE Healthcare, Chalfont, St Giles, UK).

Statistical analysis All statistical analyses were performed using IBM SPSS Statistics 20.0 (IBM Inc, NY) and managed by a statistician. Results are expressed as mean 6 standard deviation. Student t-test was used to compare GBP and SG surgical groups at M0 and at M6 and M12 after surgery. Paired t-test was used to compare the evolution of variables measured at different time points (DM6-M0, DM12-M0, and DM12-M6). Pearson correlation coefficient was used to study the association between the different continuous variables. Backward stepwise linear regression models were used to study the independent predictors of DM12-M0 TG. Full model 1 was computed among total obese subjects cohort and included DM12M0 of total apoC-II, non-HDL-apoC-II, total apoC-III, non-HDL-apoC-III, body mass index (BMI), apoB, apoA-I, fasting glucose. Full model 2 was computed among nondiabetic subjects and included the same variables as in the model 1 plus DM12-M0 HOMA-IR. All tests were 2 sided, and P , .05 was considered statistically significant.

Results Presurgery baseline demographic characteristics, fasting biochemical parameters, body composition, and energy intake of obese subjects At baseline, the GBP group was older (P , .05) and more obese (P , .05) compared with the SG group. There were more patients with diabetes and the fasting plasma glucose was higher in the GBP compared with the SG group (P , .05 for all). We found no significant differences in sex ratio, energy intake, fat mass, lipid, apolipoprotein, and hormonal profiles between GBP and SG groups (Table 1).

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Table 1 Mean baseline demographic characteristics, fasting biochemical parameters, body composition, and energy intake in the GBP and SG groups of obese subjects

Age (y) Sex ratio (F/M [% women]) Weight (kg) BMI (kg/m2) Type II diabetics, n Fasting glucose (mmol/L) HOMA-IR (nondiabetic cohort) Adiponectin (mg/mL) TG (mmol/L) TC (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) ApoA-I (g/L) ApoB (g/L) ApoC-II (mg/L) ApoC-III (mg/L) Energy intake (kJ/d) Fat mass (%)

GBP (n 5 61)

SG (n 5 71)

46.2 6 9.6 43/18 (70.5)

42.3 6 11.5 57/14 (80.3)

124.6 6 21.6 44.9 6 6.4 24 6.8 6 3.2

115.7 6 16.5b 42.4 6 5.3a a 15 5.8 6 1.7a

6.09 6 4.44 5.88 1.53 4.77 1.08 3.17 1.45 0.95 43.85 116.26 8853 50.9

6 6 6 6 6 6 6 6 6 6 6

3.69 0.98 0.83 0.34 0.75 0.22 0.20 14.48 42.70 3257 5.1

a

5.06 6 3.21 6.56 1.60 4.82 1.11 3.12 1.49 0.96 41.21 121.50 9239 50.4

6 6 6 6 6 6 6 6 6 6 6

3.47 0.95 0.83 0.34 0.65 0.22 0.18 18.64 58.21 3403 4.9

Apo, apolipoprotein; BMI, body mass index; GBP, gastric bypass; HDL-C, high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; LDL-C, low-density lipoproteincholesterol; SG, sleeve gastrectomy; TC, total cholesterol; TG, triglycerides. Data are means 6 standard deviation. Mean data were compared in presurgery (M0) between GBP and SG groups (aP , .05; bP , .01).

Effects of bariatric surgery on BMI, insulin resistance, adiponectin, body composition, and energy intake When we compared presurgery to postsurgery (1 month before vs 6 or 12 months after surgery: DM6-M0 or DM12M0) parameters, we found a significant and similar reduction in weight, BMI, plasma fasting glucose, HOMA-IR, energy intake, and fat mass and a significant and similar increase in adiponectin after surgery in both GBP and SG groups (P , .001 for all these parameters except DM6-M0 for HOMA-IR in GBP, P , .01; Table 2).

Effects of bariatric surgery on plasma lipids In DM6-M0 and DM12-M0 analyses of plasma lipid concentrations, we found a significant and similar reduction in plasma TG after surgery in both GBP (P , .01 at M6 and P , .001 at M12) and SG groups (P , .001 at M6 and M12) and a significant and similar increase in HDL-C at M12 in both GBP (P , .01) and SG (P , .001) groups. At M6, HDL-C increased significantly only in the SG group (P , .05; Table 3).

We found a significant reduction in plasma TC and LDL-C only in the GBP group at M6 and M12 (P , .01 for TC and P , .001 for LDL-C; Table 3).

Effects of bariatric surgery on apolipoproteins and distribution of apoC-III and apoC-II in HDL and non-HDL fractions After surgery, there was a significant reduction in plasma apoB in the GBP group at M6 (P , .01) and M12 (P , .001) and in the SG group only at M12 (P , .05) and the reduction in apoB was significantly greater in the GBP compared with the SG group at M6 and M12 (P , .05 for both). ApoA-I decreased significantly in the GBP group at M6 (P , .01) but with no change at M12 compared with presurgery and increased significantly in the SG group at M12 only (P , .01). Between M6 and M12, apoA-I increased significantly in both groups (P , .001; Table 3). In DM6-M0 and DM12-M0 analyses, we found a significant and similar reduction in total apoC-III, total apoC-II, non-HDL-apoC-III, HDL-apoC-III, and apoC-III/ apoC-II ratio after surgery in both GBP and SG groups. In DM12-M6, there was a significant increase in HDL-apoCIII in GBP (P , .05) and reduction in non-HDL-apoC-III in SG (P , .01). There was a significant reduction in HDLapoC-II in DM12-M0 in both groups (P , .01), in DM6M0 in the SG (P , .01) and in DM12-M6 in the GBP group (P , .05) and a significant reduction in non HDL-apoC-II in DM12-M0 in the SG group (P , .01). There were no significant reductions in plasma apoC-III, apoC-II, or apoCIII/apoC-II ratio in DM12-M6 in either group (Tables 3 and 4). In statistical analyses of the total group of obese subjects undergoing either bariatric surgical procedure, we found a significant reduction in plasma apoC-III and apoC-II in DM6-M0 (228% and 29% respectively; P , .001 and P , .01 respectively), in DM12-M0 (231% and 218% respectively; P , .001 for both) but a significant reduction only for apoC-II in DM12-M6 (P , .05; Fig. 1, Table 5). When we compared the concentrations of apoC-III and apoC-II in non-HDL and HDL fractions for the total group of obese subjects, we found a significant reduction of apoCIII in non-HDL and HDL fractions at M6 and M12 (P , .001 for all). In DM12-M6-specific analyses, we found a significant reduction in non-HDL-apoC-III (P , .05) and a significant increase in HDL-apoC-III (P , .01). For apoC-II, we found a significant reduction in non-HDL and HDL fractions at M6 (P , .05 for both) and at M12 (P , .01 for both) but no change in DM12-M6 (Fig. 2A and B, Table 5). When we considered the distribution of apoC-III between non-HDL and HDL fractions, we found no change at M6 of apoC-III distribution between fractions (55% at M0 vs 55% at M6 for non-HDL-apoC-III fraction and 45% at M0 vs 45% at M6 for HDL-apoC-III fraction). In DM12M6 analysis, we found a significant change in the

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ApoC-III reduction and redistribution after bariatric surgery

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Table 2 Mean presurgery (M0) and postsurgery evolution at 6 months (M6) and at 12 months (M12) of weight, BMI, insulin resistance, adiponectin, energy expenditure, and energy intake in the GBP and SG groups of obese subjects GBP M0

SG DM6-M0

Weight (kg) 124.6 6 21.6 228.0 6 BMI (kg/m2) 44.9 6 6.4 210.0 6 Fasting glucose (mmol/L) 6.8 6 3.2 21.3 6 HOMA-IR (nondiabetic 6.09 6 4.44 23.85 6 cohort) Adiponectin (mg/mL) 5.88 6 3.69 2.41 6 Energy intake (kJ/d) 8853 6 3257 24420 6 Fat mass (%) 50.9 6 5.1 27.81 6

DM12-M0 b

10.3 3.3b 2.6b 4.72a

235.6 212.64 21.3 23.39

6 6 6 6

DM6-M0

M0 b

14.5 4.8b 2.3b 3.19b

2.94b 4.25 6 4.59b b 3361 23914 6 3621b 3.47b 212.28 6 5.92b

115.7 42.4 5.8 5.06

6 6 6 6

16.5 5.3c 1.7c 3.21

d

228.2 210.3 20.8 23.15

6 6 6 6

DM12-M0 b

9.1 3.2b 1.6b 2.43b

232.24 211.81 20.9 23.53

6 6 6 6

12.0b 4.42b 1.4b 2.70b

6.56 6 3.47 2.17 6 2.85b 4.39 6 4.16b b 9239 6 3403 24642 6 3169 24333 6 3470b 50.4 6 4.9 28.64 6 4.05b 212.21 6 5.26b

BMI, body mass index; GBP, gastric bypass; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment-insulin resistance; SG, sleeve gastrectomy. Data are means 6 standard deviation. Mean data were compared between presurgery (M0) and postsurgery (M6 or M12) in each group (aP , .01; b P , .001) and between GBP and SG groups (cP , .05; dP , .01).

distribution of apoC-III between fractions (55% at M0 vs 50% at M12 for non-HDL-apoC-III fraction and 45% at M0 vs 50% at M12 for HDL-apoC-III fraction; P , .01 for both). For apoC-II, we found no change in non-HDL and HDL distribution between pre- and postsurgery (Fig. 2A and B, Table 5).

Presurgery (M0), postsurgery (M12) and delta post- vs pre-surgery (DM12-M0) correlations between lipids, apolipoproteins, biochemical, body composition, and energy intake parameters in the total cohort of obese subjects M0 and M12 univariate analyses are presented in Supplementary Tables 2 and 3 respectively. In DM12-M0 univariate analyses, we found strong positive associations between DTG and DapoC-III, DnonHDL-apoC-III, DHDL-apoC-III, DapoC-II, Dnon HDLapoC-II, and DHDL-apoC-II (r . 0.45 and P , .001 for all). There was a significant positive association between DHDL-C and Dadiponectin (r 5 0.304 and P , .01) and a significant negative association between DHDL-C and DBMI (r 5 20.223 and P , .05; Table 6). In DM12-M0 multivariate regression model analyses, DapoC-III in model 1 (total obese cohort) explained 56% of TG variation (full model adjusted R2 5 0.582; final model adjusted R2 5 0.556) and DapoC-III and DapoA-I in model 2 (nondiabetic cohort) explained 71% of TG variation (full model adjusted R2 5 0.689; final model adjusted R2 5 0.713; Table 7).

Discussion In the present study, we report the effects of 2 types of bariatric surgery (GBP and SG) on apoC-III that include a marked reduction in plasma apoC-III, non-HDL-apoC-III,

and HDL-apoC-III concentrations and a redistribution of apoC-III from non-HDL to HDL fraction, consistent with an improved lipid profile. Here, the marked and similar reductions in BMI, fat mass, energy intake and the improvement in insulin sensitivity after bariatric surgery in both GBP and SG groups were accompanied by a significant reduction in fasting plasma TG and an increase in HDL-C. These findings confirm the results of several studies and metaanalyses in short-term (6–12 months) and long-term ($12 months) follow-up after bariatric surgery.32,37 We found a specific decrease in plasma TC and LDL-C after GBP but not after SG. These findings are in keeping with other studies showing that mixed malabsorptive and restrictive surgery (GBP) is more effective than restrictive surgery (SG) in reducing cholesterol levels37,38 and more specifically that TC and LDL-C are significantly reduced 12 months after GBP but not after SG.39 In malabsorptive surgery, it has been shown that intestinal cholesterol absorption decreases leading to decreased plasma TC and LDL-C concentrations, accompanied by enhanced hepatic cholesterol synthesis and catabolism.40 In the present study, the greater reduction in total apoB in GBP compared with SG could be explained by a specific reduction of LDL particle numbers in GBP. Our findings are in keeping with the recently published scientific statement on lipids and bariatric procedures.41,42 In a recent lipoprotein kinetic study, we have shown improved TRL metabolism after bariatric surgery (GBP and SG) in nondiabetic, obese, insulin-resistant humans with normolipidemia or mild dyslipidemia. This improvement was manifested by decreased production of VLDL and chylomicrons and increased clearance of VLDL.33 VLDL and chylomicrons are overproduced in insulin-resistant subjects compared with healthy controls,6,7,43–46 and this overproduction seems to result, in part, from decreased sensitivity to the acute inhibitory effect of insulin on

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Table 3

Mean presurgery (M0) and postsurgery evolution at 6 months (M6) and at 12 months (M12) of lipid and apolipoprotein parameters in the GBP and SG groups of obese subjects GBP

SG DM6-M0

M0 1.53 4.77 1.08 3.17 1.45 0.95 43.85 116.26 2.72

6 6 6 6 6 6 6 6 6

0.98 0.83 0.34 0.75 0.22 0.20 14.48 42.70 0.84

20.42 20.41 0.03 20.39 20.08 20.10 23.78 234.42 20.62

6 6 6 6 6 6 6 6 6

b

0.93 0.83b 0.23 0.72c 0.16b 0.21b 12.36a 33.89c 0.74c

20.44 20.44 0.15 20.57 0.04 20.15 27.82 232.84 20.38

6 6 6 6 6 6 6 6 6

DM12-M6 c

0.66 1.01b 0.31b 0.88c 0.18 0.20c 12.78c 33.00c 0.74b

20.13 0.08 0.21 20.13 0.15 20.02 22.63 21.08 0.12

6 6 6 6 6 6 6 6 6

DM6-M0

M0 0.49 0.83 0.21c 0.72 0.15c 0.17 10.29 27.82 0.44

1.60 4.82 1.11 3.12 1.49 0.96 41.21 121.50 3.08

6 6 6 6 6 6 6 6 6

0.95 0.83 0.34 0.65 0.22 0.18 18.64 58.21 0.91d

20.50 0.05 0.10 0.03 20.01 20.02 24.15 232.10 20.66

DM12-M0 6 6 6 6 6 6 6 6 6

c

0.75 0.83e 0.31a 0.67e 0.17d 0.15d 13.79a 41.51c 0.84c

20.64 0.08 0.21 0.03 0.11 20.07 27.64 238.15 20.49

6 6 6 6 6 6 6 6 6

DM12-M6 c

0.73 0.90e 0.34c 0.83e 0.22b 0.18a,d 13.53c 45.07c 0.91c

20.08 0.03 0.15 20.03 0.12 20.03 21.43 20.13 0.19

6 6 6 6 6 6 6 6 6

0.36 0.65 0.21c 0.62 0.19c 0.13 9.96 20.66 0.82

Apo, indicates apolipoprotein; GBP, gastric bypass; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SG, sleeve gastrectomy; TC, total cholesterol; TG, triglycerides. Data are means 6 standard deviation. Mean data were compared between presurgery (M0) and postsurgery (M6 or M12) and between postsurgery (M6 and M12) in each group (aP , .05; bP , .01; c P , .001) and between GBP and SG groups (dP , .05; eP , .01).

Table 4 Mean presurgery (M0) and postsurgery evolution at 6 months (M6) and at 12 months (M12) of apoC-II and apoC-III in HDL and non-HDL fractions in the GBP and SG groups of obese subjects GBP

SG

M0 HDL-apoC-II (mg/L) non HDL-apoC-II (mg/L) HDL-apoC-III (mg/L) non HDL-apoC-III (mg/L)

27.13 15.60 52.56 64.64

6 6 6 6

8.89 8.93 24.13 25.39

D M6-M0

D M12-M0

21.05 21.43 217.12 218.21

24.90 21.99 212.27 220.30

6 6 6 6

8.48 9.31 19.14c 24.15c

6 6 6 6

D M12-M6 b

8.75 8.73 16.64c 19.82c

22.26 21.13 3.79 24.23

6 6 6 6

D M6-M0

M0 a

6.46 8.48 11.01a 22.95

26.38 15.93 56.39 65.85

6 6 6 6

11.30 8.88 32.69 32.68

22.63 22.18 216.85 215.91

6 6 6 6

D M12-M0 b

9.06 8.50 25.09c 25.26c

24.37 24.15 215.75 224.62

6 6 6 6

D M12-M6 b

9.90 8.28b 27.80c 28.58c

20.49 21.20 3.96 26.66

6 6 6 6

7.96 8.27 13.92 14.40b

Apo, apolipoprotein; GBP, gastric bypass; HDL, high-density lipoprotein; NS, not significant; SG, sleeve gastrectomy. Data are means 6 standard deviation. Mean data were compared between presurgery (M0) and postsurgery (M6 or M12) and between postsurgery (M6 and M12) in each group (aP , .05; bP , .01; c P , .001) and between GBP and SG groups (NS).

Journal of Clinical Lipidology, Vol -, No -, - 2017

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TG (mmol/L) TC (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) ApoA-I (g/L) ApoB (g/L) ApoC-II (mg/L) ApoC-III (mg/L) ApoC-III/ApoC-II ratio

DM12-M0

607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662

Maraninchi et al 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718

ApoC-III reduction and redistribution after bariatric surgery

Figure 1 ApoC-III and apoC-II in presurgery (M0) and in postsurgery (at 6 months [M6] and at 12 months [M12]) in the total cohort of obese subjects. Data are means 6 standard error of the mean. Mean data were compared between presurgery (M0) and postsurgery (M6 and M12) and between M12 and M6 after surgery (*P , .05; †P , .01; ‡P , .001). Apo, apolipoprotein.

VLDL and chylomicron secretion.5 Moreover, reduced activity of LPL has been shown in insulin-resistant subjects compared with control subjects in fasting and postprandial states.47,48 This reduction in lipolytic activity seems also to be related to insulin resistance, insulin being a potent activator of LPL.49 In the present study, the marked improvement in insulin sensitivity after bariatric surgery and its effects on TRL production and LPL activity could explain the decrease in plasma TG concentrations. Hypertriglyceridemia is a major factor contributing to HDL catabolism and to the increased formation of atherogenic small and dense LDL particles.49 The decrease in plasma TG could partly explain the increase in HDL-C after surgery. Our univariate analyses showed a significant negative association between TG and HDL-C at M0 and M12. Our multivariate regression model analysis confirmed the significant and negative association between the changes (DM12-M0) in

7

plasma TG and apoA-I (model 2). We found a positive association between plasma TG and HOMA-IR and a negative association between HDL-C and HOMA-IR at M6 and M12 after surgery. Moreover, it has been shown in subjects with abdominal obesity that the fractional catabolic rate (FCR) of apoA-I is independently associated with both catabolism and production of VLDL1-TG.50 We also found a significant positive association between the increase in plasma adiponectin and the increase in HDL-C (DM12-M0). A significant negative correlation has already been reported between HDL-apoA-I catabolism and plasma adiponectin, independent of insulin resistance and plasma lipids, suggesting as in our study a direct effect of adiponectin on HDL metabolism.49 We found a marked, significant reduction of total plasma apoC-III and non-HDL-apoC-III concentrations after GBP and SG and strong positive associations between plasma apoC-III or non-HDL-apoC-III and plasma TG in M0, M12, and DM12-M0 univariate analyses. There are various explanations accounting for the relationship between the reduction in TRL and apoC-III after bariatric surgery. One possibility is that the reduction in TRL production and the increase in TRL catabolism previously shown after bariatric surgery, in the context of weight loss and a clear improvement in insulin sensitivity,33 may lead to a reduction of apoC-III, which is mainly bound to TRL. This explanation may also apply to the parallel significant reduction of total plasma apoC-II and non-HDLapoC-II after GBP and SG and the strong positive associations between plasma apoC-II or non-HDL-apoC-II and plasma TG in M0, M12, and DM12-M0 analyses, despite the stimulating role of apoC-II on TRL catabolism. ApoC-III and apoC-II are bound to the same lipoproteins, mainly TRL and HDL, and we found a strong positive association between all the following parameters: plasma apoC-III, non-HDL-apoC-III, plasma apoC-II, non-HDLapoC-II levels in M0, M12, and DM12-M0 analyses. An alternative explanation is that the reduction in nonHDL-apoC-III after bariatric surgery could partly explain the reduction in plasma TG by the actions of apoC-III on TRL metabolism. First, apoC-III has been shown to

Table 5 Mean presurgery (M0) and postsurgery evolution at 6 months (M6) and at 12 months (M12) of apoC-II and apoC-III in plasma, HDL, and non-HDL fractions in the total cohort of obese subjects DM6-M0

M0 ApoC-II (mg/L) HDL-apoC-II (mg/L) Non-HDL-apoC-II (mg/L) ApoC-III (mg/L) HDL-apoC-III (mg/L) Non-HDL-apoC-III (mg/L)

42.50 26.72 15.78 119.96 54.66 65.30

6 6 6 6 6 6

16.43 10.23 8.87 51.29 29.08 29.50

23.74 21.91 21.84 233.94 216.97 216.97

DM12-M0 6 6 6 6 6 6

13.09b 8.79a 8.85a 37.88c 22.46c 24.67c

27.71 24.64 23.07 236.72 214.12 222.60

6 6 6 6 6 6

DM12-M6 12.92c 9.29b 8.53b 38.64c 23.21c 24.84c

22.52 21.35 21.17 21.58 3.88 25.46

6 6 6 6 6 6

9.88a 7.28 8.32 23.03 12.49b 19.02a

Apo, apolipoprotein; HDL, high-density lipoprotein. Data are means 6 standard deviation. Mean data were compared between presurgery (M0) and postsurgery (M6 or M12) and between postsurgery (M6 and M12) in the total cohort of obese subjects (aP , .05; bP , .01; cP , .001).

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719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774

Journal of Clinical Lipidology, Vol -, No -, - 2017

8 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830

Figure 2 ApoC-III (A) and apoC-II (B) in HDL and non-HDL fractions in presurgery (M0) and in postsurgery (at 6 months [M6] and at 12 months [M12]) in the total cohort of obese subjects. Data are means 6 standard error of the mean. Mean data were compared between presurgery (M0) and postsurgery (M6 and M12) and between M12 and M6 after surgery (*P , .05; †P , .01; ‡P , .001). Apo, apolipoprotein; HDL, high-density lipoprotein.

promote hepatic VLDL1 production.18 ApoC-III is mainly synthesized in the liver and its expression is suppressed by insulin51 and stimulated by glucose.52 Here, the significant decrease of fasting glucose and the improvement of insulin sensitivity after GBP and SG could have played a role in reducing hepatic apoC-III expression, with subsequent reduction in VLDL1 production. Second, it is well known that apoC-III is an inhibitor of LPL activity.19 Third, several studies have shown that apoC-III inhibits receptor-mediated uptake of TRL by the liver.21,22 Kinetic studies using tracer methodology have confirmed that VLDL-apoC-III is overproduced in overweight insulin-resistant subjects,15 in hypertriglyceridemic subjects compared with controls,53 and in centrally, obese men compared with controls.54 Increased plasma concentrations of apoC-III are associated with impaired VLDL1 clearance in obese insulin-resistant men55 and VLDLapoC-III clearance is reduced in centrally obese men compared with controls.54 Furthermore, plasma TG concentrations in abdominal obesity are determined by the kinetics of VLDL1 particles, their catabolism being mainly dependent on apoC-III concentration56 and apoC-III levels have been identified as significant determinants of the kinetics and plasma concentrations of TRLs.57 VLDLapoC-III concentration was also shown to be positively, independently, and significantly associated with HDLapoA-I clearance.54 We found a significant decrease of non HDL-apoC-III, which inhibits LPL, and of non-HDLapoC-II, which stimulates LPL. However, the reduction in non-HDL-apoC-III was clearly higher than that in non-HDL-apoC-II for both GBP and SG at M6 and M12, leading to a significant reduction in total plasma apoCIII/apoC-II ratio after surgery. For the total cohort, the decrease in non-HDL-apoC-III was also higher than that

of non-HDL-apoC-II (226% vs 212% at M6 and 235% vs 220% at M12). Our DM12-M0 multivariate regression model analyses confirmed the strong and significant positive association between plasma TG and total plasma apoC-III (models 1 and 2), apoC-III being the strongest predictor of TG variation after surgery. From all these data, we suggest that the marked reduction in plasma apoC-III or more particularly non-HDL-apoC-III after bariatric surgery might have contributed to the improvement of TRL metabolism, that is, decreased production and increased clearance of TRL, leading to a reduction in plasma TG and an increase in HDL-C. Both of the previously mentioned changes (ie, reductions in TRL and apoC-III) could occur concurrently, with one affecting the other. Reductions in TRL secondary to marked reductions in body weight, energy intake, and insulin resistance post-bariatric surgery reduce the concentration of apoC-III bound to the TRL fraction. Redistribution of apoC-III from TRL to HDL fractions after bariatric surgery may further contribute to this reduction in TRLassociated apoC-III. Reductions in TRL-bound apo-CIII in turn play an active role in contributing to further reductions in TRL concentrations. Definitive proof of a bidirectional causative relationship between TRL and apoC-III reductions awaits further mechanistic study. Change occurring in the distribution of apoC-III between non-HDL and HDL fractions is another important finding of our study. Here, we confirmed the results of several studies showing that apoC-III levels associated with TRL in the fasted state are increased in hypertriglyceridemic subjects.13,58 After a parallel decrease in apoC-III in non-HDL and HDL fractions with no change in the distribution of apoC-III between non-HDL (55%) and HDL (45%) fractions at M6 after surgery, we found a divergent

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831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886

887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 Maraninchi et al

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TC TG HDL-C LDL-C ApoC-II HDL-apoC-II Non-HDL-apoC-II ApoC-III HDL-apoC-III Non-HDL-apoC-III ApoA-I ApoB BMI Fasting glucose HOMA-IR (nondiabetic cohort) Adiponectin Fat mass Energy intake

TC

TG

HDL-C

LDL-C

ApoC-II

HDL-apoC-II

Non-HDL-apoC-II

ApoC-III

HDL-apoC-III

Non-HDL-apoC-III

0.360c 0.257a 0.888c 0.384c 0.449c 0.180 0.283b 0.360c 0.199 0.312b 0.845c 20.039 0.247a 20.232 0.058 0.021 20.106

20.072 0.144 0.618c 0.490c 0.465c 0.712c 0.681c 0.535c 0.010 0.327b 20.041 0.097 0.028 20.004 20.056 0.151

0.049 0.003 0.081 20.087 0.075 0.129 0.035 0.654c 0.005 20.223a 0.100 20.184 0.304b 20.203 20.080

0.248a 0.315b 0.072 0.098 0.125 0.041 0.144 0.835c 0.022 0.224a 20.155 20.017 0.052 20.212

0.752c 0.696c 0.760c 0.643c 0.602c 0.040 0.477c 20.057 0.121 20.091 20.065 20.017 0.090

0.050 0.530c 0.517c 0.341b 0.035 0.452c 0.030 0.052 0.004 20.107 0.058 0.099

0.568c 0.383c 0.523c 0.033 0.268a 20.088 0.113 20.115 0.073 20.195 20.025

0.789c 0.819c 0.169 0.344b 20.075 0.180 20.084 20.002 0.073 0.093

0.293b 0.197 0.297b 20.029 0.128 0.062 0.092 0.041 0.206

0.067 0.296b 20.100 0.139 20.202 20.056 20.067 0.039

ApoC-III reduction and redistribution after bariatric surgery

Table 6 Delta postsurgery vs presurgery (DM12-M0) Pearson correlations between lipids, apolipoproteins, biochemical, body composition, and energy intake parameters in the total cohort of obese subjects

Apo, indicates apolipoprotein; BMI, body mass index; HDL-C, high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; TG, triglycerides. Data are Pearson correlation coefficients (aP , .05; bP , .01; cP , .001). Light gray 5 positive correlations and dark gray 5 negative correlations.

9 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998

Journal of Clinical Lipidology, Vol -, No -, - 2017

10 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054

Table 7 Multiple linear regression models predicting delta M12-M0 triglycerides evolution (final model after backward stepwise selection with a threshold for exclusion at P , .05) Regression 95% confidence coefficient interval Model 1 (n 5 81) Delta M12-M0, per 1 unit increase ApoC-III 0.012 Constant 20.050 Model 2 (n 5 41) Delta M12-M0, per 1 unit increase ApoC-III 0.016 ApoA-I 20.697 Constant 0.143

0.010 to 0.015

P value

,.001

0.013 to 0.019 ,.001 21.254 to 20.14 .016

Apo, apolipoprotein. Full model 1 was computed among total obese cohort subjects and included DM12-M0 of apoC-II, non-HDL-apoC-II, apoC-III, non-HDLapoC-III, BMI, apoB, apoA-I, fasting glucose (full model adjusted R2 5 0.582; final model adjusted R2 5 0.556). Full model 2 was computed among nondiabetic subjects and included the same variables as model 1 and DM12-M0 HOMA-IR (full model adjusted R2 5 0.689; final model adjusted R2 5 0.713).

evolution of the distribution of apoC-III in non-HDL and HDL between M6 and M12 after surgery with a significant increase in HDL-apoC-III (14%) and a significant decrease in non-HDL-apoC-III (25%) in the total cohort. These changes led to a redistribution of apoC-III from non-HDL (decreasing from 55% to 50%) to HDL (increasing from 45% to 50%) fractions without a significant change in total plasma apoC-III concentrations. As already discussed, apoC-III concentrations play an important role in TRL metabolism but also in HDL metabolism. Indeed, it has been shown in nonobese subjects that HDL-apoC-III concentration was positively associated with HDL-apoA-I concentration and inversely with HDL-apoA-I FCR.59 Moreover, HDL-apoC-III production rate was correlated with HDL-apoA-I concentration and resident time in healthy subjects.60 In another study, HDL-apoC-III concentration was significantly elevated in centrally obese men compared with nonobese men and was significantly and directly correlated with production rate but also FCR of HDL-apoA-I in centrally obese men. Both VLDL apoCIII and HDL-apoC-III concentrations were positively associated with HDL-apoA-I hypercatabolism independently of BMI and insulin resistance.54 One can speculate that the quantitative and relative redistribution of apoC-III between TRL and HDL fractions after bariatric surgery, leading to an improved apoC-III distribution profile in lipoproteins, may have contributed to the improvement in TRL and HDL metabolism and finally to the reduction in plasma TG and the increase in HDL-C. Selective oligonucleotide antisense inhibition of apoC-IIII synthesis are currently

being developed. This therapy causes a marked reduction in plasma apoC-III and TG concentration and an increase in HDL-C, highlighting the major role of apoC-III in TRL and HDL metabolism.61 Moreover, the efficiency of this treatment in TG reduction in familial chylomicronemia syndrome with LPL activity below 5% also underlines the role of apoC-III as a key regulator of LPL-independent pathways of TG metabolism.62 In conclusion, we have described, the evolution of apoCIII after bariatric surgery in humans. We showed, for the first time, marked reduction of total plasma apoC-III and non-HDL-apoC-III occurring after both GBP and SG. These quantitative changes were associated with a redistribution of apoC-III between TRL and HDL fractions consistent with a better lipid profile. Reduction of apoCIII and its lipoprotein redistribution after bariatric surgery may have implications in dyslipidemia improvement and could contribute to the reduction in cardiovascular morbidity and mortality that has been demonstrated after this effective treatment of obesity. Beyond a better understanding of the apoC-III role in the dyslipidemia of insulinresistant subjects, the present study could help the physicians to choose among other parameters the most appropriate bariatric surgery procedure depending on the lipid profile before surgery. Moreover, this study has confirmed apoC-III as an attractive clinical target in the fields of hypertriglyceridemia, atherogenic dyslipidemia, and cardiovascular disease.

Acknowledgments The authors wish to thank Myriam Coffin for her technical assistance. Funding: This work was supported by an AORC Excellence (AP-HM-2010). Disclosure: All authors have participated in the research and/or article preparation. The paper has been read and approved by all authors. Conflict of interest: The authors declare no conflict of interest.

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37. 38.

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1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222

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1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334

Maraninchi et al 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390

ApoC-III reduction and redistribution after bariatric surgery

Appendix Supplementary Table 1 Presurgery (M0) antidiabetic and hypolipidemic treatments in the GBP and SG groups of obese subjects

Lifestyle counseling alone Oral antidiabetic drugs Insulin Oral antidiabetic drugs and insulin Statin Fibrate Fibrate and ezetimibe

GBP (n 5 61)

SG (n 5 71)

1 16 1 6 12 0 2

2 8 2 3 7 2 0

GBP, gastric bypass; SG, sleeve gastrectomy. Data are numbers of subjects treated with anti-diabetic and hypolipidemic treatment at pre-surgery (M0) in GBP and SG groups.

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12.e1 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446

1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 Presurgery (M0) Pearson correlations between lipids, apolipoproteins, biochemical, body composition, and energy intake parameters in the total cohort of TG

HDL-C

LDL-C

ApoC-II

HDL-apoC-II

Non-HDL-apoC-II

ApoC-III

HDL-apoC-III

Non-HDL-apoC-III

0.321c 0.294b 0.819c 0.424c 0.395c 0.363c 0.458c 0.476c 0.396c 0.262b 0.723c 0.002 0.142 20.042 0.230b 0.089 20.102

20.255b 0.101 0.694c 0.521c 0.702c 0.736c 0.712c 0.605c 20.127 0.510c 0.013 0.377c 0.190 20.148 20.190 0.175

0.026 20.017 0.090 20.140 0.036 0.075 20.06 0.737c 20.098 20.101 20.011 20.293a 0.500c 0.200 20.210a

0.154 0.120 0.184a 0.150 0.143 0.174 0.022 0.709c 0.155 0.079 0.007 0.050 0.090 20.233a

0.881c 0.837c 0.773c 0.760c 0.598c 20.077 0.461c 20.011 0.366c 0.067 20.104 20.162 0.255a

0.478c 0.639c 0.703c 0.416c 20.062 0.340c 0.059 0.257b 0.103 0.003 20.133 0.235a

0.662c 0.569c 0.597c 20.136 0.470c 0.000 0.348c 0.005 20.142 20.044 0.139

0.874c 0.877c 0.121 0.425c 20.092 0.344c 0.026 0.083 20.174 0.234a

0.533c 0.137 0.417c 20.001 0.381c 0.091 0.011 20.086 0.232a

0.046 0.370c 20.097 0.214a 20.042 0.121 20.155 0.251a

Apo, apolipoprotein; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides. Data are Pearson correlation coefficients (aP , .05; bP , .01; cP , .001). Light gray 5 positive correlations and dark gray 5 negative correlations.

Journal of Clinical Lipidology, Vol -, No -, - 2017

FLA 5.4.0 DTD  JACL1075_proof  15 March 2017  5:40 pm

TC TG HDL-C LDL-C ApoC-II HDL-apoC-II Non-HDL-apoC-II ApoC-III HDL-apoC-III Non-HDL-apoC-III ApoA-I ApoB BMI Fasting glucose HOMA-IR (nondiabetic cohort) Adiponectin Fat mass Energy intake

TC

12.e2

Supplementary Table 2 obese subjects

1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558

1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614 Postsurgery (M12) Pearson correlations between lipids, apolipoproteins, biochemical, body composition, and energy intake parameters in the total cohort of TG

HDL-C

LDL-C

ApoC-II

HDL-apoC-II

Non-HDL-apoC-II

ApoC-III

HDL-apoC-III

Non-HDL-apoC-III

0.336b 0.260a 0.944c 0.412c 0.378c 0.339b 0.443c 0.478c 0.306b 0.351c 0.889c 20.055 20.017 0.317a 0.200a 0.096 0.055

20.332b 0.228a 0.680c 0.613c 0.571c 0.731c 0.630c 0.660c 20.054 0.424c 0.128 0.370c 0.503c 20.250a 20.050 0.089

0.049 20.013 0.013 20.064 0.068 0.203 20.051 0.799c 20.031 20.162 20.303b 20.378b 0.518c 0.094 20.146

0.315b 0.288b 0.273b 0.246a 0.305b 0.131 0.184 0.910c 20.061 0.019 0.319a 0.113 0.104 0.053

0.907c 0.836c 0.739c 0.724c 0.604c 0.084 0.478c 0.160 0.301b 0.451b 20.095 0.038 0.030

0.526c 0.691c 0.729c 0.539c 0.122 0.402c 0.205 0.325b 0.454b 20.144 0.090 0.093

0.606c 0.511c 0.565c 20.017 0.434c 0.04 0.225a 0.374b 20.040 20.050 20.033

0.867c 0.908c 0.331b 0.412c 0.156 0.236a 0.543c 0.076 0.105 0.057

0.578c 0.390c 0.382c 0.074 0.219a 0.413b 0.126 0.055 20.029

0.193 0.323b 0.141 0.213a 0.522c 0.046 0.077 0.088

Apo, apolipoprotein; BMI, body mass index; HDL-C, high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; TG, triglycerides. Data are Pearson correlation coefficients (aP , .05; bP , .01; cP , .001). Light gray 5 positive correlations and dark gray 5 negative correlations.

ApoC-III reduction and redistribution after bariatric surgery

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TC TG HDL-C LDL-C ApoC-II HDL-apoC-II Non-HDL-apoC-II ApoC-III HDL-apoC-III Non-HDL-apoC-III ApoA-I ApoB BMI Fasting glucose HOMA-IR (nondiabetic cohort) Adiponectin Fat mass Energy intake

TC

Maraninchi et al

Supplementary Table 3 obese subjects

12.e3 1615 1616 1617 1618 1619 1620 1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670