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Peroxisome Proliferator-activated Receptors and Hepatic Stellate Cell Activation

2000; Elsevier BV; Volume: 275; Issue: 46 Linguagem: Inglês

10.1074/jbc.m006577200

1083-351X

Takeo Miyahara, Laura W. Schrum, Richard A. Rippe, Shigang Xiong, Hal F. Yee, Kenta Motomura, Frank A. Anania, Timothy M. Willson, Hidekazu Tsukamoto,

Endoplasmic Reticulum Stress and Disease

The present study examined the roles of peroxisome proliferator-activated receptors (PPAR) in activation of hepatic stellate cells (HSC), a pivotal event in liver fibrogenesis. RNase protection assay detected mRNA for PPARγ1 but not that for the adipocyte-specific γ2 isoform in HSC isolated from sham-operated rats, whereas the transcripts for neither isoforms were detectable in HSC from cholestatic liver fibrosis induced by bile duct ligation (BDL). Semi-quantitative reverse transcriptase-polymerase chain reaction confirmed a 70% reduction in PPARγ mRNA level in HSC from BDL. Nuclear extracts from BDL cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-κB and AP-1 binding were increased. Treatment of cultured-activated HSC with ligands for PPARγ (10 μm15-deoxy-Δ 12,14 -PGJ 2 (15dPGJ 2 ); 0.1∼10 μm BRL49653) inhibited DNA and collagen synthesis without affecting the cell viability. Suppression of HSC collagen by 15dPGJ 2 was abrogated 70% by the concomitant treatment with a PPARγ antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPARα and γ (>100 μm) but not at those that only activate PPARα (<10 μm) or by a synthetic PPARα-selective agonist (GW9578). 15dPGJ 2 reduced α1(I) procollagen, smooth muscle α-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ 2 and BRL49653 inhibited α1(I) procollagen promoter activity. Tumor necrosis factor α (10 ng/ml) reduced PPARγ mRNA, and this effect was prevented by the treatment with 15dPGJ 2 . These results demonstrate that HSC activation is associated with the reductions in PPARγ expression and PPAR-responsive element binding in vivo and is reversed by the treatment with PPARγ ligands in vitro . These findings implicate diminished PPARγ signaling in molecular mechanisms underlying activation of HSC in liver fibrogenesis and the potential therapeutic value of PPARγ ligands for liver fibrosis.