Regulation of hepatic fatty acid elongase 5 by LXRalpha-SREBP-1c.
Dietary essential fatty acids linoleic acid and alpha-linolenic acid are converted to arachidonic-, eicosapentaenoic-, and docosahexaenoic acid under tight regulation by nutritional status and hormones. Hepatic fatty acid elongase 5 (Elovl5) elongates C18-20 polyunsaturated fatty acids (PUFAs) and is important for biosynthesis of C20-22 PUFAs. We demonstrate that Liver X Receptor alpha (LXRalpha) and sterol regulatory binding protein-1c (SREBP-1c) regulate hepatic Elovl5 expression. LXRalpha and LXRbeta play different roles in maintenance of basal expression of Elovl5. LXRalpha is necessary for basal as well as LXR agonist induced Elovl5 transcription. Promoter studies revealed that the mouse Elovl5 gene is a direct SREBP-1c target. The up-regulation of Elovl5 expression by LXR agonist is likely secondary to the induction of SREBP-1c. PUFAs repress expression of SREBP-1c and Elovl5, but when combined with LXR ligand stimulation, which increases SREBP-1c mRNA and nuclear SREBP-1c, Elovl5 mRNA levels are restored to normal. Our studies suggest that an LXRalpha-SREBP-1c pathway plays a regulatory role in hepatic biosynthesis of PUFAs through transcriptional activation of Elovl5 as well as other desaturases. The stimulatory role of LXRalpha-SREBP-1c in the production of PUFAs enables the possibility for a feedback regulation of hepatic lipogenesis through PUFA mediated repression of SREBP-1c expression.
Qin
Yan
Y
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO.Box. 1046 Blindern, N-0316 Oslo, Norway.
Dalen
Knut Tomas
KT
Gustafsson
Jan-Ake
JA
Nebb
Hilde I
HI
D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D000081031:Fatty Acid Elongases; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D018197:Hepatoblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000123:Acetyltransferases; D004268:DNA-Binding Proteins; D000081031:Fatty Acid Elongases; D005231:Fatty Acids, Unsaturated; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C000630954:ELOVL5 protein, human; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides