Ameliorated Hepatic Insulin Resistance Is Associated with Normalization of Microsomal Triglyceride Transfer Protein Expression and Reduction in Very Low Density Lipoprotein Assembly and Secretion in the Fructose-fed Hamster

Abstract

To determine whether reduction of insulin resistance could ameliorate fructose-induced very low density lipoprotein (VLDL) oversecretion and to explore the mechanism of this effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted insulinmediated suppression of the glucose production rate and to a ϳ2-fold increase in whole body insulin-mediated glucose disappearance rate (p < 0.001). Rosiglitazone ameliorated the defect in hepatocyte insulin-stimulated tyrosine phosphorylation of the insulin receptor, IRS-1, and IRS-2 and the reduced protein mass of IRS-1 and IRS-2 induced by fructose feeding. Protein-tyrosine phosphatase 1B levels were increased with fructose feeding and were markedly reduced by rosiglitazone. Rosiglitazone treatment led to a ϳ50% reduction of VLDL secretion rates (p < 0.05) in vivo and ex vivo. VLDL clearance assessed directly in vivo was not significantly different in the FR (fructose-fed ؉ rosiglitazone-treated) versus F (fructose-fed ؉ placebo-treated) hamsters, although there was a trend toward a lower clearance with rosiglitazone. Enhanced stability of nascent apolipoprotein B (apoB) in fructose-fed hepatocytes was evident, and rosiglitazone treatment resulted in a significant reduction in apoB stability. The increase in intracellular mass of microsomal triglyceride transfer protein seen with fructose feeding was reduced by treatment with rosiglitazone. In conclusion, improvement of hepatic insulin signaling with rosiglitazone, a peroxisome proliferator-activated receptor ␥ agonist, is associated with reduced hepatic VLDL assembly and secretion due to reduced intracellular apoB stability.The typical dyslipidemia of insulin-resistant states and Type 2 diabetes consists of hypertriglyceridemia due to VLDL 1 overproduction, low high density lipoprotein cholesterol, and small dense low density lipoprotein particles (1). Elevated plasma free fatty acid (FFA) flux from peripheral and intra-abdominal adipose tissue depots due to resistance to the insulin antilipolytic and esterification effect in adipose tissue is felt to play an important role in driving VLDL assembly and secretion in insulin resistant states (2-4). Nevertheless, previous studies in humans suggest that insulin also has an important direct effect on the liver in controlling VLDL secretion (5-7).Rat and mouse models of insulin resistance and type 2 diabetes have provided important insights into the molecular mechanisms of insulin resistance. These animal models may not, however, be ideal for the study of human lipoprotein disorders because, unlike humans, their livers secrete both apoB48 and apoB100-containing VLDL, and they do not necessarily develop VLDL oversecretion as the basis for their hypertriglyceridemia (8, 9). Unlike livers from rat or mouse, the liver of the golden Syrian hamster secretes only apoB100-containing VLDL, and its lipoprotein metabolism more closely resembles that of humans (10). We have shown that insulin resistance in the fru...

The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients

“…Since there were no changes in the cholesterol present in VLDL, it seems reasonable that improved fasting triglyceride involves a reduction in hepatic triglyceride synthesis or its integration into apo-B100, both processes being influenced by insulin [28,29].…”

Overproduction of intestinal lipoprotein containing apolipoprotein B-48 in Psammomys obesus: impact of dietary n-3 fatty acids

“…Although the physiological basis of metabolic dyslipidaemia appears to be hepatic overproduction of apo-B-containing VLDL particles [46,47], emerging evidence suggests that intestinal overproduction of apo-B-48-containing lipoproteins in insulin-resistant states may be an important contributor to the elevation of circulating triglyceride-rich lipoproteins [17,18,48]. The present study demonstrated that intestinal cells, like hepatocytes [49,50], responded to n-3 FA and decreased the output of triglyceride-rich lipoproteins by lowering the synthesis of apo B-48 and by inhibiting the new formation of lipids.…”

Overproduction of large VLDL particles is driven by increased liver fat content in man

“…Insulin acts on two key factors that regulate the initiation of VLDL assembly and the maturation of VLDL particles: microsomal triglyceride transfer protein and phosphatidylinositol 3-kinase [37][38][39][40]. Consequently, impaired insulin signalling results in increased VLDL production.…”