Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance - Evidence for enhanced lipoprotein assembly, reduced intracellular apoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overprodu ction of very low density Lipoprotein (VLDL) in the insulin resistant state . Fructose feeding for a a-week period induced significant hypertriglycerid emia and hyperinsulinemia, and the development of whole body insulin resist ance was documented using the euglycemic-hyperinsulinemic clamp technique. In vivo Triton WR-1339 studies showed evidence of VLDL-apoB overproduction in the fructose-fed hamster. Fructose feeding induced a significant increas e in cellular synthesis and secretion of total triglyceride (TG) as well as VLDL-TG by primary hamster hepatocytes, Increased TG secretion was accompa nied by a 4.6-fold increase in VLDL-apoB secretion. Enhanced stability of n ascent apoB in fructose-fed hepatocytes mas evident in intact cells as well as in a permeabilized cell system, Analysis of newly formed lipoprotein pa rticles in hepatic microsomes revealed significant differences in the patte rn and density of lipoproteins, with hepatocytes derived from fructose-fed hamsters having higher levels of luminal lipoproteins at a density of VLDL versus controls, Immunoblot analysis of the intracellular mass of microsoma l triglyceride transfer protein, a key enzyme involved in VLDL assembly sho wed a striking 2.1-fold elevation in hepatocytes derived from fructose-fed versus control hamsters, Direct incubation of hamster hepatocytes with vari ous concentrations of fructose failed to show any direct stimulation of its intracellular stability or extracellular secretion, further supporting the notion that the apoB overproduction in the fructose-fed hamster may be rel ated to the fructose-induced insulin resistance in this animal model. In su mmary, hepatic VLDL-apoB overproduction in fructose-fed hamsters appears to result from increased intracellular stability of nascent apoB and an enhan ced expression of MTP, which act to facilitate the assembly and secretion o f apoB-containing lipoprotein particles.