title: 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 PPAR-target 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 6α) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for β-oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte TG lipase (ATGL) and comparative gene identification 58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some (pyruvate dehydrogenase kinase 4 and fibroblast 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 PPARβ-dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPARβ agonist (GW0742) decreased (14)C-18:2,n-6 in TGs but did not affect β-oxidation. These studies establish that Elovl5 activity regulates hepatic levels of FAs controlling PPARβ activity, ATGL expression, and TG catabolism, but not FA oxidation.
authors.affiliation: School of Biological and Population Health Sciences and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Tripathy
authors.affiliation: School of Biological and Population Health Sciences and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331.
authors.forename: Kelli A
authors.initials: KA
authors.lastname: Lytle
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710.
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center, Boston, MA 02111.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
authors.affiliation: Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY 10032.
authors.forename: Li-Shin
authors.initials: LS
authors.lastname: Huang
authors.affiliation: School of Biological and Population Health Sciences and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Jump
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D059865:Endoplasmic Reticulum Stress; D000081031:Fatty Acid Elongases; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048068:PPAR-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*; D010636:Phenols; D013438:Sulfhydryl Compounds; D000217:Acyltransferases
chemical_list: D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D008049:Lipase; D048068:PPAR-beta; D013844:Thiazoles; D014280:Triglycerides; C000630954:ELOVL5 protein, human; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C581235:Elovl5 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: adipocyte triglyceride lipase; fatty acid oxidation; fatty liver; peroxisome proliferator-activated receptor β; pyruvate dehydrogenase kinase 4