title: Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic 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 hyperinsulinemic-euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C-ϵ 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.
  
  
  CONCLUSIONS
  These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536-8012, USA.
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.forename: Francois R
authors.initials: FR
authors.lastname: Jornayvaz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kanda
authors.forename: Violeta
authors.initials: V
authors.lastname: Popov
authors.forename: David W
authors.initials: DW
authors.lastname: Frederick
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.forename: Blas
authors.initials: B
authors.lastname: Guigni
authors.forename: Kalyani G
authors.initials: KG
authors.lastname: Bharadwaj
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Jae-Hak
authors.initials: JH
authors.lastname: Park
authors.forename: Kitt F
authors.initials: KF
authors.lastname: Petersen
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000821:Animal Feed; D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D053305:Apolipoprotein C-III / Q000097:blood* / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006946:Hyperinsulinism / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D065626:Non-alcoholic Fatty Liver Disease; D019518:Postprandial Period / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D053299:Apolipoprotein B-100; D053305:Apolipoprotein C-III; D001786:Blood Glucose; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D004075:Diglycerides; D014280:Triglycerides; D011493:Protein Kinase C