Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity.
Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice establish that PPARalpha was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Delta(5) desaturase (Delta(5)D), Delta(6)D, and Delta(9)D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Delta(5)D, Delta(6)D, and Delta(9)D. Only Delta(9)D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of l-type pyruvate kinase, Delta(9)D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Delta(9)D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lep(ob/ob)), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Delta(9)D expression and the massive accumulation of monounsaturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARalpha, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition.
Wang
Yun
Y
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Botolin
Daniela
D
Xu
Jinghua
J
Christian
Barbara
B
Mitchell
Ernestine
E
Jayaprakasam
Bolleddula
B
Nair
Muraleedharan G
MG
Nair
Muraleedharan
M
Peters
Jeffrey M
JM
Peters
Jeffery M
JM
Busik
Julia V
JV
Busik
Julia
J
Olson
L Karl
LK
Jump
Donald B
DB
D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044943:Fatty Acid Desaturases / Q000235:genetics* / Q000378:metabolism; D000081031:Fatty Acid Elongases; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000123:Acetyltransferases; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D044943:Fatty Acid Desaturases; D000081031:Fatty Acid Elongases; D005947:Glucose; D006845:Hydrocarbons, Fluorinated; D007328:Insulin; D020738:Leptin; D047493:PPAR alpha; D011743:Pyrimidines; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C000630954:ELOVL5 protein, human; C000630955:ELOVL6 protein, human; C000630968:Elovl6 protein, mouse; C442825:Mlxipl protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C006253:pirinixic acid