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J. Biol. Chem., Vol. 283, Issue 8, 4866-4876, February 22, 2008

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Peroxisome Proliferator-activated Receptor Deficiency Abolishes the Response of Lipogenic Gene Expression to Re-feeding

RESTORATION OF THE NORMAL RESPONSE BY ACTIVATION OF LIVER X RECEPTOR ^*

Abdel M. Hebbachi, Brian L. Knight, David Wiggins, Dilip D. Patel, and Geoffrey F. Gibbons¹

From the Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ and the Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, London W12 0NN, United Kingdom

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

Received for publication, November 19, 2007

^* This work was supported by a Medical Research Council (MRC) Programme Grant (to G. F. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: OCDEM, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK. Tel.: 44-0-1865-857224; Fax: 44-0-1865-857217; E-mail: geoff.gibbons{at}mrl.ox.ac.uk.

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