Both insulin resistance and diabetes in Psammomys obesus upregulate the hepatic machinery involved in intracellular VLDL assembly.
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.


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.
Zoltowska
M
M
Centre de Recherche, Hôpital Sainte-Justine, Department of Nutrition, Université de Montréal, Montréal, Québec, Canada.
Ziv
E
E
Delvin
E
E
Lambert
M
M
Seidman
E
E
Levy
E
E
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005849:Gerbillinae; D022781:Hepatocytes / Q000378:metabolism; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D007976:Leupeptins / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex
D001055:Apolipoproteins B; D007328:Insulin; D007976:Leupeptins; D008079:Lipoproteins, VLDL; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; C063261:acetylleucyl-leucyl-norleucinal; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine