Effects of Bariatric Surgery on Hepatic and Intestinal Lipoprotein Particle Metabolism in Obese, Nondiabetic Humans

Abstract

T he prevalence of obesity is steadily increasing so much, so that obesity has become a pandemic in developed and developing nations. 1 The increased risk of morbidity and mortality and more particularly of atherosclerotic cardiovascular disease associated with obesity and insulin-resistant states is of great public health concern.2,3 Each 5 kg/m 2 increase above a body mass index (BMI) of 25 kg/m 2 results in a 40% increase in cardiovascular mortality.3 Dyslipidemia is a prominent feature of obesity and insulin-resistant states. 4 The typical dyslipidemia associated with these conditions is mainly characterized by elevated plasma triglyceride concentration, low high-density lipoprotein-cholesterol (HDL-C) level, increased proportion of small and dense low-density lipoprotein (LDL), and postprandial hyperlipidemia.4,5 These abnormalities contribute to the high residual cardiovascular risk observed in obesity and insulin-resistant states, even if low LDL-C levels are achieved by statin treatment.6,7 The pathophysiology of this dyslipidemia is widely explained by the blood accumulation of triglyceride-rich lipoproteins (TRL) from the liver (apolipoprotein [apo]B-100-containing very low-density lipoprotein [VLDL]) and the intestine (apoB-48-containing chylomicrons). This accumulation has been attributed to the © 2014 American Heart Association, Inc. Objective-The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. Approach and Results-Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRLapoB-48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of pati...

Liraglutide Reduces Postprandial Hyperlipidemia by Increasing ApoB48 (Apolipoprotein B48) Catabolism and by Reducing ApoB48 Production in Patients With Type 2 Diabetes Mellitus

“…This method is considered to evaluate correctly postprandial lipid metabolism. [39][40][41] We are confident that the different protocol designs performed in humans (constant feeding state) and in mice (oral fat load) do not confound interpretation of the results generated because they have been shown to give similar information in previous studies. For instance, it has been shown, in humans, that treatment with atorvastatin-induced a significant reduction of ApoB48 pool in a kinetic study performed in constant feeding 39 and a significant decrease in ApoB48 incremental AUC after an oral fat load.…”

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

“…Sustained weight loss also delays the onset of T2D, in which the atherogenic dyslipidemia complex is often a prevalent feature. Bariatric surgery, the most effective intervention in inducing sustained weight loss, also reduces TRL production (132,133). Nonpharmacological therapies thus far have not shown reductions in CVD outcomes.…”

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

“…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][44][45][46] and this overproduction seems to result, in part, from decreased sensitivity to the acute inhibitory effect of insulin on 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 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 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.…”

“…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.…”

“…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.…”