title: A role for PPARalpha in the control of SREBP activity and lipid synthesis in the liver.
abstract: Inclusion of the PPARalpha (peroxisome-proliferator-activated receptor alpha) activator WY 14,643 in the diet of normal mice stimulated the hepatic expression of not only genes of the fatty acid oxidation pathway, but also those of the de novo lipid synthetic pathways. Induction of fatty acid synthase mRNA by WY 14,643 was greater during the light phase of the diurnal cycle, when food intake was low and PPARalpha expression was high. Hepatic fatty acid pathway flux in vivo showed a similar pattern of increases. The abundance of mRNAs for genes involved in hepatic cholesterol synthesis was also increased by WY 14,643, but was associated with a decrease in cholesterogenic carbon flux. None of these changes were apparent in PPARalpha-null mice. Mice of both genotypes showed the expected decreases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels and cholesterol synthesis in response to an increase in dietary cholesterol. The increase in fatty acid synthesis due to WY 14,643 was not mediated by increased expression of SREBP-1c (sterol regulatory element binding protein-1c) mRNA, but by an increase in cleavage of the protein to the active form. An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation.
authors.affiliation: MRC Clinical Sciences Centre, Faculty of Medicine Imperial College, Hammersmith Hospital, London W12 ONN, UK. brian.knight@csc.mrc.ac.uk
authors.forename: Brian L
authors.initials: BL
authors.lastname: Knight
authors.forename: Abdel
authors.initials: A
authors.lastname: Hebbachi
authors.forename: David
authors.initials: D
authors.lastname: Hauton
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Brown
authors.forename: David
authors.initials: D
authors.lastname: Wiggins
authors.forename: Dilip D
authors.initials: DD
authors.lastname: Patel
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Gibbons
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D002791:Cholesterol, Dietary / Q000494:pharmacology; D002940:Circadian Rhythm / Q000235:genetics; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D008055:Lipids / Q000096:biosynthesis* / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002791:Cholesterol, Dietary; D004852:Epoxy Compounds; D005227:Fatty Acids; D008055:Lipids; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D020033:Protein Isoforms; D011743:Pyrimidines; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C006253:pirinixic acid; D002784:Cholesterol; C054207:etomoxir