出版社:American Society for Biochemistry and Molecular Biology
摘要:Fatty acid elongases and desaturases play an important rolein hepatic and whole body lipid composition. We examined therole that key transcription factors played in the control ofhepatic elongase and desaturase expression. Studies with peroxisomeproliferator-activated receptor (PPAR)-deficient mice establishthat PPAR was required for WY14643-mediated induction of fattyacid elongase-5 (Elovl-5), Elovl-6, and all three desaturases[5 desaturase (5D), 6D, and 9D]. Increased nuclear sterol-regulatoryelement binding protein-1 (SREBP-1) correlated with enhancedexpression of Elovl-6, 5D, 6D, and 9D. Only 9D was also regulatedindependently by liver X receptor (LXR) agonist. Glucose inductionof L-type pyruvate kinase, 9D, and Elovl-6 expression requiredthe carbohydrate-regulatory element binding protein/MAX-likefactor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and9D expression in livers of streptozotocin-induced diabetic ratsand high fat-fed glucose-intolerant mice correlated with lowlevels of nuclear SREBP-1. In leptin-deficient obese mice (Lepob/ob),increased SREBP-1 and MLX nuclear content correlated with theinduction of Elovl-5, Elovl-6, and 9D expression and the massiveaccumulation of monounsaturated fatty acids (18:1,n-7 and 18:1,n-9)in neutral lipids. Diabetes- and obesity-induced changes inhepatic lipid composition correlated with changes in elongaseand desaturase expression. In conclusion, these studies establisha role for PPAR, LXR, SREBP-1, ChREBP, and MLX in the controlof hepatic fatty acid elongase and desaturase expression andlipid composition.Supplementary key words peroxisome proliferator-activated receptor • sterol-regulatory element binding protein-1 • carbohydrate-regulatory element binding protein • MAX-like factor X • liver X receptor
Abbreviations: ACC, acetyl-coenzyme A carboxylase; ChoRE, carbohydrate-regulatory element; ChREBP, carbohydrate-regulatory element binding protein; 5D, 5 desaturase; Elovl-1, fatty acid elongase-1; HNF-4, hepatic nuclear factor-4; L-PK, L-type pyruvate kinase; Luc, luciferase; LXR, liver X receptor; MLX, MAX-like factor X; PPAR, peroxisome proliferator-activated receptor ; qRT, quantitative real-time; SREBP-1, sterol-regulatory element binding protein-1; T1317, T0901317; T3, triiodothyronine