Fasting and Postprandial Overproduction of Intestinally Derived Lipoproteins in an Animal Model of Insulin Resistance

Abstract

Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.The metabolic syndrome, which is characterized by fasting hypertriglyceridemia, insulin resistance, glucose intolerance, hypertension, and obesity (1), appears also to include impaired postprandial lipoprotein metabolism (2, 3). Postprandial triglyceride-rich lipoproteins and especially chylomicron remnants have been implicated as risk factors for atherosclerosis and progression of coronary artery disease, based on both experimental work (4, 5) and cross-sectional studies (6 -8). Emerging evidence suggest that intestinal lipoproteins may be particularly atherogenic in diabetes (9). We (10, 11) and others (12-15) have shown previously that there is an elevation of postprandial triglyceride (TG) 1 -rich lipoproteins in subjects with insulin resistance and type 2 diabetes and that fasting hypertriglyceridemia predicts this abnormal postprandial response to a fat load. A strong correlation also exists between plasma insulin and the postprandial TG response to a fat meal, and the postprandial levels of large VLDLs and chylomicron remnants (3, 16). In the fasting state, plasma insulin, a marker of insulin resistance, is also related to fasting plas...

Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes

“…23 The consequences of the insulin signaling defect at the level of the enterocyte are an increase in de novo lipogenesis and chylomicron assembly and secretion. 23,29,30 We also confirmed the results of several studies in animal models of insulin resistance 22,31,32 in type 2 diabetic 20 and obese, insulin-resistant human subjects, 21 showing that the acute inhibitory effect of insulin on hepatic TRL-apoB-100 production is blunted.The kinetic parameters of our study are different (lower PS and PR and higher FCR) with regard to those of the only kinetic study on TRL-apoB-48 metabolism in type 2 diabetic subjects versus controls, 8 but several differences between the 2 studies may explain these discrepancies. The diabetic population in that study was more insulin resistant (mean HOMA-IR: 5.6 versus 4.4) and was frankly more hypertriglyceridemic (mean fasting plasma TG levels: 4.6 versus 2.0 mmol/L) than our diabetic population.…”

Chylomicron remnants are increased in the postprandial state in CD36 deficiency

“…This enhanced production of FFAs might induce the de novo lipogenesis of TG, resulting in the increased synthesis of intestine-derived lipoproteins. Haidari et al (28) showed that the de novo synthesis of FA and apoB-48-containing lipoproteins in the intestine of fructose-fed hamsters was increased. Even though this result was observed in an animal model of insulin resistance model, it was suggested that the endogenous production of fatty acids might influence the apoB-48-containing lipoprotein secretion in the small intestine.…”

Diabetic dyslipidaemia: from basic research to clinical practice*

“…The induction of the insulin resistant state in fructose-fed hamsters is associated with overproduction of apo B 48 containing particles [91]. There is also evidence that intestinal MTP is increased in diabetic animals and this could enhance the formation of apo B 48 containing particles [86,91]. Further studies are needed to delineate the exact contribution of intestinal overproduction of apo B 48 lipoproteins in diabetes to the postprandial lipemia in humans.…”