Peroxisome Proliferator-activated Receptor α Deficiency Abolishes the Response of Lipogenic Gene Expression to Re-feeding: RESTORATION OF THE NORMAL RESPONSE BY ACTIVATION OF LIVER X RECEPTOR α

• Published in: The Journal of biological chemistry 2008-02, Vol.283 (8), p.4866-4876
• Main Authors: Hebbachi, Abdel M, Knight, Brian L, Wiggins, David, Patel, Dilip D, Gibbons, Geoffrey F
• Format: Article
• Language: English
• Subjects: Adenoviridae; Adenovirus; Animals; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fatty Acid Synthase, Type I - biosynthesis; Fatty Acid Synthase, Type I - genetics; Food Deprivation - physiology; Insulin - blood; Lipid Metabolism - physiology; Liver - metabolism; Liver X Receptors; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Mutant Strains; Orphan Nuclear Receptors; PPAR gamma - genetics; PPAR gamma - metabolism; Rats; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Stearoyl-CoA Desaturase - biosynthesis; Stearoyl-CoA Desaturase - genetics; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Transduction, Genetic
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M709471200

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 α (LXRα). 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 α (PPARα)-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 PPARα-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 PPARα-deficient mice. Rat hepatocytes transfected with an adenovirus encoding a dominant negative form of PPARα were resistant to the stimulatory effects of insulin on Fas and Scd-1 mRNA expression in vitro. When LXRα 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 PPARα deficiency was abolished during re-feeding. However, although re-feeding the LXRα 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 PPARα-deficient mice. We conclude that intact PPARα 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 LXRα.