PPARgamma  suppresses proximal alpha 1(I) collagen promoter via inhibition of p300-facilitated NF-I binding to DNA in hepatic stellate cells

doi:10.1074/jbc.M510094200

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Papers In Press, published online ahead of print October 10, 2005
J. Biol. Chem, 10.1074/jbc.M510094200
Submitted on September 14, 2005
Accepted on October 10, 2005

PPAR $gamma$ suppresses proximal $alpha$ 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

Pathology Dept., Keck School of Medicine of USC, Los Angeles, CA 90089-9141

Corresponding Author: htsukamo{at}usc.edu

Depletion of peroxisome proliferator-activated receptor $gamma$ (PPAR $gamma$ ) represents one of the key molecular changes that underlie transdifferentiation (activation) of hepatic stellate cells (HSC) in the genesis of liver fibrosis (Miyahara T, et al. J Biol Chem 275: 35715-22; Hazra S, et al. J. Biol Chem 279:11392-401, 2004). In support of this notion, treatment with PPAR $gamma$ ligands or ectopic expression of PPAR $gamma$ suppresses HSC activation markers, most notably expression of $alpha$ 1(I) procollagen. However, the mechanisms underlying this anti-fibrotic effect are largely unknown. The present study utilized deletion-reporter gene constructs of proximal 2.2kb $alpha$ 1(I) procollagen promoter to demonstrate that a region proximal to –133bp is where PPAR $gamma$ exerts its inhibitory effect. Within this region, two DNase footprints with overlapping NF1 and Sp1 sites exist. NF-I independently stimulates the promoter activity and synergistically promotes Sp1-induced activity. PPAR $gamma$ inhibits NF-I binding to the most proximal footprint (-97/-85bp) and inhibits its transactivity. The former effect is mediated by PPAR $gamma$ ’s ability to inhibit p300-facilitated NF1 binding to DNA as demonstrated by chromatin immunoprecipitation assay.

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PPAR suppresses proximal 1(I) collagen promoter via inhibition of p300-facilitated NF-I binding to DNA in hepatic stellate cells

PPAR $gamma$ suppresses proximal $alpha$ 1(I) collagen promoter via inhibition of p300-facilitated NF-I binding to DNA in hepatic stellate cells