Tripathy Sasmita, Lytle Kelli A, Stevens Robert D, Bain James R, Newgard Christopher B, Greenberg Andrew S, Huang Li-Shin, Jump Donald B
School of Biological and Population Health Sciences and the Linus Pauling Institute, Oregon State University, Corvallis, OR 97331.
Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710.
J Lipid Res. 2014 Jul;55(7):1448-64. doi: 10.1194/jlr.M050062. Epub 2014 May 9.
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.
非酒精性脂肪性肝病是肥胖和2型糖尿病群体中的一个主要公共卫生问题。高脂猪油饮食可诱导C57BL/6J小鼠肥胖和脂肪肝，并抑制PPAR靶基因脂肪酸延长酶5（Elovl5）的表达。Elovl5在单不饱和脂肪酸和多不饱和脂肪酸合成中起关键作用。增加肥胖小鼠肝脏中的Elovl5活性可降低肝脏甘油三酯和内质网应激标志物（X盒结合蛋白1和cAMP依赖性转录因子6α），并增加甘油三酯分解代谢和脂肪酰肉碱。肝脏Elovl5活性增加并未提高肝脏的β氧化能力。Elovl5对肝脏甘油三酯分解代谢的影响与脂肪细胞甘油三酯脂肪酶（ATGL）和比较基因识别58（CGI58）的蛋白水平增加有关。肝脏Elovl5活性升高还诱导了一些（丙酮酸脱氢酶激酶4和成纤维细胞生长因子21）但不是其他细胞色素P450 4A10（CYP4A10）、PPAR靶基因的表达。在人HepG2细胞中，Elovl5活性的脂肪酸产物通过PPARβ依赖性机制增加ATGL而非CGI58的mRNA水平。用PPARβ激动剂（GW0742）处理小鼠AML12肝细胞可降低甘油三酯中的（14）C-18:2，n-6，但不影响β氧化。这些研究表明，Elovl5活性调节肝脏脂肪酸水平，控制PPARβ活性、ATGL表达和甘油三酯分解代谢，但不影响脂肪酸氧化。
