Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice

Abstract

Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. The high-fat lard diet induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPARtarget gene, FA elongase 5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepatic Elovl5 activity in obese mice lowered hepatic TGs and endoplasmic reticulum stress markers (X-box binding protein 1 and cAMP-dependent transcription factor 6 ) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for -oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte TG lipase (ATGL) and comparative gene identifi cation 58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some (pyruvate dehydrogenase kinase 4 and fi broblast growth factor 21), but not other cytochrome P450 4A10 (CYP4A10 ), PPAR-target genes. FA products of Elovl5 activity increased ATGL, but not CGI58, mRNA through PPAR -dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPAR agonist (GW0742) decreased 14 C-18:2,n-6 in TGs but did not affect -oxidation. These studies establish that Elovl5 activity regulates hepatic levels of FAs controlling PPAR activity, ATGL expression, and TG catabolism, but not FA oxidation. -Tripathy, S., K. A. Lytle, R. D. Stevens, J. R. Bain, C. B. Newgard, A. S. Greenberg, L-S. Huang, and D. B. Jump. Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice. J. Lipid Res . 2014. 55: 1448-1464. © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.