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J. Biol. Chem., Vol. 280, Issue 49, 40650-40659, December 9, 2005

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Peroxisome Proliferator-activated Receptor Suppresses Proximal 1(I) Collagen Promoter via Inhibition of p300-facilitated NF-I Binding to DNA in Hepatic Stellate Cells^*

Sharon Yavrom, Li Chen, Shigang Xiong, Jiaohong Wang, Richard A. Rippe, and Hidekazu Tsukamoto¶1

From the Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, the Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7032, and the ^¶Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073

Depletion of peroxisome proliferator-activated receptor (PPAR) represents one of the key molecular changes that underlie transdifferentiation (activation) of hepatic stellate cells in the genesis of liver fibrosis (Miyahara, T., Schrum, L., Rippe, R., Xiong, S., Yee, H. F., Jr., Motomura, K., Anania, F. A., Willson, T. M., and Tsukamoto, H. (2000) J. Biol. Chem. 275, 35715-35722; Hazra, S., Xiong, S., Wang, J., Rippe, R. A., Krishna, V., Chatterjee, K., and Tsukamoto, H. (2004) J. Biol. Chem. 279, 11392-11401). In support of this notion, ectopic expression of PPAR suppresses hepatic stellate cells activation markers, most notably expression of 1(I) procollagen. However, the mechanisms underlying this antifibrotic effect are largely unknown. The present study utilized deletion-reporter gene constructs of proximal 2.2-kb 1(I) procollagen promoter to demonstrate that a region proximal to -133 bp is where PPAR exerts its inhibitory effect. Within this region, two DNase footprints with Sp1 and reverse CCAAT box sites exist. NF-I, but not CCAAT DNA-binding factor/NF-Y, binds to the proximal CCAAT box in hepatic stellate cells. A mutation of this site almost completely abrogates the promoter activity. NF-I mildly but independently stimulates the promoter activity and synergistically promotes Sp1-induced activity. PPAR inhibits NF-I binding to the most proximal footprint (-97/-85 bp) and inhibits its transactivity. The former effect is mediated by the ability of PPAR to inhibit p300-facilitated NF-I binding to DNA as demonstrated by chromatin immunoprecipitation assay.

Received for publication, September 14, 2005

^* 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: Keck School of Medicine of the University of Southern California, 1333 San Pablo St., MMR-402, Los Angeles, CA 90033-9141. Tel.: 323-442-5107; Fax: 323-442-3126; E-mail: htsukamo{at}usc.edu.

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