Inhibition of microsomal triglyceride transfer protein improves insulin sensitivity and reduces atherogenic risk in Zucker fatty rats

Abstract

1. Insulin-resistant states are commonly associated with a significantly higher risk of atherosclerosis. Insulin resistance has also been correlated with enhanced very low-density lipoprotein (VLDL) production, which is exacerbated by increased intestinal lipid synthesis and insulin-stimulated de novo lipogenesis. Microsomal triglyceride transfer protein (MTP) catalyses the critical step in the synthesis and secretion of VLDL and chylomicrons. The purpose of the present study was to test the hypothesis that chronic inhibition of MTP with a small molecule inhibitor would improve insulin sensitivity and reduce atherogenic risk in a genetic model of diabetic dyslipidaemia. 2. The in vivo activity of BMS-201038, a potent inhibitor of MTP, was evaluated in a model of hypertriglyceridemia induced by Triton WR1339 and corn oil in Zucker fatty rats. Triglyceride secretion rate was significantly reduced by a single dose of BMS-201038 by 35% at 0.3 mg/kg and 47% at 1 mg/kg, respectively. 3. Another group of Zucker fatty rats was dosed orally with BMS-201038 (0.3 and 1 mg/kg) for 14 days. Serum levels of triglycerides were reduced by 71% and 87%, non-esterified free fatty acids were reduced by 33% and 40%, and low-density lipoproteins by 26% and 29%, by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. These serum lipid changes were accompanied by significant improvements in glucose tolerance and insulin sensitivity. In addition, lipid peroxidation in liver was reduced by 59% and 61%, and superoxide dismutase activity was increased by 11% and 45% by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. Similar beneficial changes were found in aorta as well. 4. The present study provides evidence that inhibition of MTP with a small molecule inhibitor significantly improves dyslipidaemia associated with insulin resistance and reduces the atherosclerotic risk.

ApoE and the role of very low density lipoproteins in adipose tissue inflammation

“…Therefore, restriction of fat intake and/or inhibition of TGRL production with reduced secretion of TGRLs into blood and subsequently decreased fat influx into adipose tissue and skeletal muscle would be more beneficial in treating obesity-linked insulin resistance. Indeed, inhibition of TGRL production by an inhibitor of microsomal triglyceride transfer protein (MTP) reduced plasma TG levels and improved insulin sensitivity in obesity [26]. However, the MTP inhibitor may also cause hepatic fat accumulation [27].…”

Intestinal Lipid Handling

“…29,32 Even so, intestinal insulin sensitivity was seldom assessed in normal and pathophysiological conditions. This situation is even more peculiar when one considers that the gut (1) is being recognized as an endocrine organ 33 ; (2) is associated with a significant improvement/remission in T2D when duodenal and jejunal sections are excised 34,35 ; (3) participates actively in postprandial hyperlipidemia for the majority of the day, in which the enterocyte-derived TRL and chylomicron remnant have a central input 36,37 by affecting the cells of the artery wall via lipid deposition, 38,39 oxidative and inflammatory actions, 3,40 apoptotic/toxic effects, 41 and in the reduction of insulin sensitivity of other organs 42,43 ; and (4) may develop aberrant insulin receptor signaling at the level of the enterocyte. 15 Free radicals, generated under physiological conditions, play important beneficial roles in human physiology, including their actions as signaling molecules in a variety of cell signaling pathways, and often as second messengers.…”

ANMCO/ISS/AMD/ANCE/ARCA/FADOI/GICR-IACPR/SICI-GISE/SIBioC/SIC/SICOA/SID/SIF/SIMEU/SIMG/SIMI/SISA Joint Consensus Document on cholesterol and cardiovascular risk: diagnostic–therapeutic pathway in Italy

“…Figure 10 shows the mechanism of action of lomitapide 154 . In preclinical studies, lomitapide caused a dose-dependent decrease in VLDL and C-LDL values in the range of 19–89% and a decrease in TG in the range of 8–49% 156 , 157 . The effects of lomitapide in humans were evaluated in a Phase 3 clinical study that enrolled 29 HoFH patients with mean baseline values of C-LDL equal to 336 mg/dL.…”