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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:118.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Both Insulin Resistance and Diabetes in Psammomys obesus Upregulate the Hepatic Machinery Involved in Intracellular VLDL Assembly

M. Zoltowska; E. Ziv; E. Delvin; M. Lambert; E. Seidman; E. Levy

From the Centre de Recherche Hôpital Sainte-Justine (M.Z., E.D., M.L, E.S., E.L.); the Departments of Nutrition (M.Z., E.L.), Biochemistry (E.D.), Genetics (M.L.), and Pediatrics (E.S.), Université de Montréal, Montréal, Québec, Canada, and the Diabetes Unit (E.Z.), Division of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel.

Correspondence to Dr Emile Levy, Centre de Recherche, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine Rd, Montreal, Quebec, Canada H3T 1C5. E-mail levye{at}justine.umontreal.ca

Objective— In the current study, we examined the mechanisms that regulate hepatic apolipoprotein B (apoB)–containing lipoprotein secretion in Psammomys obesus, a good animal model for the investigation of insulin resistance and diabetes.

Methods and Results— When fed chow ad libitum, 22% maintained normoglycemia and normoinsulinemia (group A), 33% exhibited normoglycemia and appreciable hyperinsulinemia (group B), and 45% developed overt diabetes (group C). Body weight gain, plasma free fatty acid elevation, hypertriglyceridemia, and hypercholesterolemia characterized groups B and C. Triton WR-1339 injection, at fasting, resulted in higher plasma VLDL-triglyceride and VLDL-apoB accumulation in groups B and C, suggesting increased VLDL production by the liver. Pulse-chase labeling experiments in cultured hepatocytes with [³⁵S]methionine revealed reduced intracellular degradation and enhanced secretion of newly synthesized apoB in groups B and C. Concomitant with the raised triglyceride and cholesterol contents in the livers of groups B and C, there was an increase in lipogenesis and in the activity of microsomal triglyceride transfer protein, monoacylglycerol acyltransferase, and diacylglycerol transferase. Pretreatment of hepatocytes with proteasomal inhibitors eliminated the differences in apoB secretion among groups A, B, and C.

Conclusions— Our data indicate that both insulin resistance and diabetes triggered the intracellular machinery involved in VLDL assembly and secretion.

Key Words: insulin resistance • diabetes • VLDL production • apo B degradation • microsomal triglyceride transfer protein

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