Peroxisome proliferator-activated receptor alpha deficiency abolishes the response of lipogenic gene expression to re-feeding: restoration of the normal response by activation of liver X receptor alpha.
The mRNA expression of lipogenic genes Scd-1 and Fas is regulated partly by the insulin-sensitive transcription factor SREBP-1c and liver X receptor alpha (LXRalpha). Compared with normal mice, the increase in the mRNA expression of hepatic Scd-1, Fas, and Srebp-1c was severely attenuated in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice during the transition from the starved to the re-fed states. The concentration of the membrane-bound form of SREBP-1c was also lower in the livers of the PPARalpha-deficient mice during re-feeding but there was little difference in the concentration of the active, nuclear form, or in the abundance of Insig-2a mRNA. The response of plasma insulin to starvation and re-feeding was normal in the PPARalpha-deficient mice. Rat hepatocytes transfected with an adenovirus encoding a dominant negative form of PPARalpha were resistant to the stimulatory effects of insulin on Fas and Scd-1 mRNA expression in vitro. When LXRalpha was activated in vivo by inclusion of a non-steroidal ligand in the diet, the expression of the mRNA for hepatic Srebp-1c, Fas, and Scd-1 was increased severalfold in mice of both genotypes and resistance associated with PPARalpha deficiency was abolished during re-feeding. However, although re-feeding the LXRalpha ligand induced the immature form of SREBP-1c equally in the livers of both genotypes, the concentration of the nuclear form remained relatively low in the livers of the PPARalpha-deficient mice. We conclude that intact PPARalpha is required to mediate the response of Scd-1 and Fas gene expression to insulin and that this is normally achieved directly by activation of LXRalpha.
Hebbachi
Abdel M
AM
Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
Knight
Brian L
BL
Wiggins
David
D
Patel
Dilip D
DD
Gibbons
Geoffrey F
GF
D000256:Adenoviridae; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000096:biosynthesis / Q000235:genetics; D005508:Food Deprivation / Q000502:physiology*; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
D004268:DNA-Binding Proteins; C506120:Insig2 protein, mouse; D007328:Insulin; D000071518:Liver X Receptors; D008565:Membrane Proteins; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D054890:Fatty Acid Synthase, Type I