title: Treatment with atorvastatin ameliorates hepatic very-low-density lipoprotein overproduction in an animal model of insulin resistance, the fructose-fed Syrian golden hamster: evidence that reduced hypertriglyceridemia is accompanied by improved hepatic insulin sensitivity.
abstract: A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster has been previously documented to exhibit considerable hepatic very-low-density lipoprotein (VLDL) overproduction concomitant with the development of whole body insulin resistance. Here, we investigated whether hepatic lipoprotein overproduction can be ameliorated by treatment with a hydroxymethyl glutaryl conenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, using a series of ex vivo experiments. Hamsters were fed a fructose-enriched diet for 14 days to induce a state of insulin resistance, and then continued on a fructose-enriched diet supplemented with or without 40 mg/kg atorvastatin per day for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride levels. There was a significant decline in plasma triglyceride levels following supplementation with the inhibitor (50% to 59%; P <.05). Experiments with primary hepatocytes revealed a decreased VLDL-apolipoprotein B (apoB) production (37.4% +/- 10.4%; P <.05) in hamsters treated with atorvastatin. Interestingly, atorvastatin treatment partially attenuated (by 23%) the elevated hepatic level of microsomal triglyceride transfer protein (MTP) induced by fructose feeding. There was molecular evidence of improved hepatic insulin sensitivity with atorvastatin treatment based on assessment of the phosphorylation status of the insulin receptor and the expression of protein tyrosine phosphatase-1B. The improvement in insulin signaling was not mediated by a change in hepatic triglyceride accumulation as no significant difference was observed in liver triglyceride levels. Taken together, these data suggest that statins can ameliorate the VLDL-apoB overproduction state observed in a fructose-fed, insulin-resistant hamster model, and may potentially contribute to an enhanced hepatic insulin sensitivity.
authors.affiliation: Division of Clinical Biochemistry, Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Leyla
authors.initials: L
authors.lastname: Mangaloglu
authors.forename: Raphael C
authors.initials: RC
authors.lastname: Cheung
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Van Iderstine
authors.forename: Changiz
authors.initials: C
authors.lastname: Taghibiglou
authors.forename: Louisa
authors.initials: L
authors.lastname: Pontrelli
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis; D000069059:Atorvastatin; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D004195:Disease Models, Animal; D005632:Fructose / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D015228:Hypertriglyceridemia / Q000188:drug therapy*; D007333:Insulin Resistance / Q000502:physiology*; D007700:Kinetics; D008079:Lipoproteins, VLDL / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008163:Luminescent Measurements; D008647:Mesocricetus; D010766:Phosphorylation; D011758:Pyrroles / Q000627:therapeutic use*; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D001786:Blood Glucose; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D014280:Triglycerides; D005632:Fructose; D002784:Cholesterol; D000069059:Atorvastatin; D011972:Receptor, Insulin