Abstract
A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of very low density lipoprotein (VLDL) in the insulin resistant state. Fructose feeding for a 2-week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance 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 increase in cellular synthesis and secretion of total triglyceride (TG) as well as VLDL-TG by primary hamster hepatocytes. Increased TG secretion was accompanied by a 4.6-fold increase in VLDL-apoB secretion. Enhanced stability of nascent apoB in fructose-fed hepatocytes was evident in intact cells as well as in a permeabilized cell system. Analysis of newly formed lipoprotein particles in hepatic microsomes revealed significant differences in the pattern 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 microsomal triglyceride transfer protein, a key enzyme involved in VLDL assembly, showed a striking 2.1-fold elevation in hepatocytes derived from fructose-fed versus control hamsters. Direct incubation of hamster hepatocytes with various 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 related to the fructose-induced insulin resistance in this animal model. In summary, hepatic VLDL-apoB overproduction in fructose-fed hamsters appears to result from increased intracellular stability of nascent apoB and an enhanced expression of MTP, which act to facilitate the assembly and secretion of apoB-containing lipoprotein particles.
Highlights
A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of very low density lipoprotein (VLDL) in the insulin resistant state
Direct incubation of hamster hepatocytes with various concentrations of fructose failed to show any direct stimulation of its intracellular stability or extracellular secretion, further supporting the notion that the apolipoprotein B (apoB) overproduction in the fructose-fed hamster may be related to the fructose-induced insulin resistance in this animal model
Overproduction of VLDL-TG and VLDL-apoB has been well demonstrated in the insulin-resistant state in both humans and animal models, few data are available on the underlying cellular mechanisms involved, those directly affecting the apoB protein itself
Summary
A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of very low density lipoprotein (VLDL) in the insulin resistant state. The insulin resistant state is commonly associated with lipoprotein abnormalities that are risk factors for coronary heart disease, including hypertriglyceridemia, high levels of VLDL, low levels of high density lipoprotein cholesterol [8], and small, dense LDL [9] These metabolic abnormalities together with hypertension and Type 2 diabetes may cluster in the same individual, constituting a syndrome referred to as the metabolic Syndrome X [2]. Hamster liver produces VLDL containing only apoB-100 with a density close to that of human VLDL [42, 43], unlike the rat, which has been used extensively for studies of VLDL metabolism and the effects of insulin resistance, and whose liver secretes both apoB-48 and apoB100. It appears feasible to induce insulin resistance in the hamster and use the insulin-resistant hamster model to study the mechanisms controlling hepatic VLDL-apoB secretion
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