ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content

• Published in: Journal of lipid research Vol. 56; no. 3; pp. 526 - 536
• Main Authors: Camporez, João Paulo G., Kanda, Shoichi, Petersen, Max C., Jornayvaz, François R., Samuel, Varman T., Bhanot, Sanjay, Petersen, Kitt Falk, Jurczak, Michael J., Shulman, Gerald I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2015; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; apolipoprotein; Apolipoprotein A-V; Apolipoproteins - genetics; Apolipoproteins - metabolism; diacylglycerol; Dietary Fats - pharmacology; dyslipidemias; Gene Knockdown Techniques; Insulin Resistance; insulin signaling; lipase/lipoprotein; lipid uptake; Liver - metabolism; Male; Mice; Muscle, Skeletal - metabolism; nonalcoholic fatty liver disease; protein kinase C; Protein Kinase C-epsilon - genetics; Protein Kinase C-epsilon - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Triglycerides - genetics; Triglycerides - metabolism; apolipoprotein; lipid uptake; nonalcoholic fatty liver disease; insulin signaling; lipase/lipoprotein; dyslipidemias; insulin resistance; diacylglycerol; protein kinase C
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M054080

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 pho­sphory­lation 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.