title: ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content.
abstract: ApoA5 has a critical role in the regulation of plasma TG concentrations. In order to determine whether ApoA5 also impacts ectopic lipid deposition in liver and skeletal muscle, as well as tissue insulin sensitivity, we treated mice with an antisense oligonucleotide (ASO) to decrease hepatic expression of ApoA5. ASO treatment reduced ApoA5 protein expression in liver by 60-70%. ApoA5 ASO-treated mice displayed approximately 3-fold higher plasma TG concentrations, which were associated with decreased plasma TG clearance. Furthermore, ApoA5 ASO-treated mice fed a high-fat diet (HFD) exhibited reduced liver and skeletal muscle TG uptake and reduced liver and muscle TG and diacylglycerol (DAG) content. HFD-fed ApoA5 ASO-treated mice were protected from HFD-induced insulin resistance, as assessed by hyperinsulinemic-euglycemic clamps. This protection could be attributed to increases in both hepatic and peripheral insulin responsiveness associated with decreased DAG activation of protein kinase C (PKC)-ε and PKCθ in liver and muscle, respectively, and increased insulin-stimulated AKT2 pho-sphory-lation in these tissues. In summary, these studies demonstrate a novel role for ApoA5 as a modulator of susceptibility to diet-induced liver and muscle insulin resistance through regulation of ectopic lipid accumulation in liver and skeletal muscle.
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT.
authors.forename: João Paulo G
authors.initials: JPG
authors.lastname: Camporez
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kanda
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT; Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT.
authors.forename: Max C
authors.initials: MC
authors.lastname: Petersen
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT.
authors.forename: François R
authors.initials: FR
authors.lastname: Jornayvaz
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT.
authors.forename: Kitt Falk
authors.initials: KF
authors.lastname: Petersen
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Departments of Internal Medicine Yale University School of Medicine, New Haven, CT; Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT. Electronic address: gerald.shulman@yale.edu.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*
chemical_list: C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D004041:Dietary Fats; D014280:Triglycerides; C497256:Prkce protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon
keywords: apolipoprotein; diacylglycerol; dyslipidemias; insulin resistance; insulin signaling; lipase/lipoprotein; lipid uptake; nonalcoholic fatty liver disease; protein kinase C