A role for PPARalpha in the control of SREBP activity and lipid synthesis in the liver

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 syntha...

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Bibliographic Details
Published in:Biochemical journal 2005-07, Vol.389 (Pt 2), p.413
Main Authors: Knight, Brian L, Hebbachi, Abdel, Hauton, David, Brown, Anna-Marie, Wiggins, David, Patel, Dilip D, Gibbons, Geoffrey F
Format: Article
Language:English
Subjects:
Animals
Cholesterol - biosynthesis
Cholesterol, Dietary - pharmacology
Circadian Rhythm - genetics
Epoxy Compounds - pharmacology
Fatty Acids - biosynthesis
Gene Expression Regulation - drug effects
Lipids - biosynthesis
Lipids - blood
Liver - drug effects
Liver - metabolism
Male
Mice
Mice, Knockout
Peroxisome Proliferators - pharmacology
PPAR alpha - agonists
PPAR alpha - genetics
PPAR alpha - metabolism
Protein Isoforms - genetics
Protein Isoforms - metabolism
Pyrimidines - pharmacology
RNA, Messenger - metabolism
Sterol Regulatory Element Binding Protein 1 - genetics
Sterol Regulatory Element Binding Protein 1 - metabolism
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Summary: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.
ISSN:1470-8728