1. Apolipoprotein CIII Overexpressing Mice Are Predisposed to Diet-Induced Hepatic Steatosis and Hepatic Insulin Resistance
- Author
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Hui-Young Lee, Gerald I. Shulman, Ira J. Goldberg, Shoichi Kanda, Michael J. Jurczak, Dongyan Zhang, Varman T. Samuel, Andreas L. Birkenfeld, Kitt Falk Petersen, Kalyani G. Bharadwaj, Violeta B. Popov, David W. Frederick, Cheol Soo Choi, François R Jornayvaz, Blas A. Guigni, and Jae-Hak Park
- Subjects
Blood Glucose ,Male ,Fatty Liver/genetics/metabolism ,Apolipoprotein C-III/blood/genetics ,Cholesterol, VLDL ,Insulin Resistance/genetics ,AKT2 ,030204 cardiovascular system & hematology ,Hyperinsulinism/metabolism ,chemistry.chemical_compound ,Steatohepatitis/Metabolic Liver Disease ,Mice ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,Protein Kinase C ,Triglycerides/pharmacokinetics/secretion ,0303 health sciences ,Genetic Predisposition to Disease/genetics ,VLDL/metabolism/secretion ,Postprandial Period/physiology ,Postprandial Period ,Mutant Strains ,Cholesterol ,Apolipoprotein B-100/metabolism ,Apolipoprotein B-100 ,Female ,Diglycerides/metabolism ,medicine.medical_specialty ,Protein Kinase C/metabolism ,Biology ,Diglycerides ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,Hyperinsulinism ,medicine ,Animals ,Genetic Predisposition to Disease ,Protein kinase A ,Triglycerides ,030304 developmental biology ,Diacylglycerol kinase ,Apolipoprotein C-III ,Blood Glucose/metabolism ,Hepatology ,Triglyceride ,medicine.disease ,Animal Feed ,Dietary Fats ,Mice, Mutant Strains ,Fatty Liver ,Dietary Fats/pharmacology ,Endocrinology ,chemistry ,Steatosis ,Insulin Resistance - Abstract
Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high-fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemiceuglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C- activation, and decreased insulin-stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD-fed ApoC3Tg mice could be attributed to a � 70% increase in hepatic triglyceride uptake and � 50% reduction hepatic triglyceride secretion. Conclusion: These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance. (HEPATOLOGY 2011;54:1650-1660)
- Published
- 2011