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 PPAR␥1 but not that for the adipocyte-specific ␥2 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 transcriptasepolymerase chain reaction confirmed a 70% reduction in PPAR␥ mRNA level in HSC from BDL. Nuclear extracts from BDL cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-B and AP-1 binding were increased. Treatment of culturedactivated HSC with ligands for PPAR␥ (10 M 15-deoxy-⌬ 12,14 -PGJ 2 (15dPGJ 2 ); 0.1ϳ10 M 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 PPAR␥ antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPAR␣ and ␥ (>100 M) but not at those that only activate PPAR␣ (<10 M) or by a synthetic PPAR␣-selective agonist (GW9578). 15dPGJ 2 reduced ␣1(I) procollagen, smooth muscle ␣-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ 2 and BRL49653 inhibited ␣1(I) procollagen promoter activity. Tumor necrosis factor ␣ (10 ng/ml) reduced PPAR␥ mRNA, and this effect was prevented by the treatment with 15dPGJ 2 . These results demonstrate that HSC activation is associated with the reductions in PPAR␥ expression and PPAR-responsive element binding in vivo and is reversed by the treatment with PPAR␥ ligands in vitro. These findings implicate diminished PPAR␥ signaling in molecular mechanisms underlying activation of HSC in liver fibrogenesis and the potential therapeutic value of PPAR␥ ligands for liver fibrosis.

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Cirrhosis is the most important consequence of alcoholic liver disease for which liver transplantation is the only treatment option available. Transdifferentiation of hepatic stellate cells (HSC) to myofibroblastic cells (MF) is a central event in liver fibrogenesis, and understanding molecular mechanisms that underlie this cellular event provides pivotal insights into development of new therapeutic modalities for cirrhosis. To this end, the authors proposed several years ago that transdifferentiation of quiescent HSC to MF may be causally associated with transcriptional regulation known for adipocyte-preadipocytic fibroblast dedifferentiation. In support of this notion, the authors showed that adipogenic transcription factors and their downstream adipocyte specific genes are expressed abundantly in quiescent HSC and that this expression profile is lost in HM. Further, gain-of-function manipulations for adipogenic transcription factors such as peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and sterol regulatory element binding protein-1c have been shown to reverse culture-induced MF to quiescent HSC. The authors also demonstrated that tumor necrosis factor-alpha and Wnt, known mediators of anti-adipogenesis, also suppress the activity of PPAR-gamma and contribute to HSC-MF transdifferentiation. These results reinforce the concept of adipogenic regulation essential to the quiescent phenotype and the loss of such regulation underlying HSC-HM transdifferentiation. They also provide insights into the molecular basis for the use of PPAR-gamma agonists, which has been advocated for treatment of liver fibrosis.

Tannase-producing S. lugdunensis is associated with advanced-stage colon cancer, and the tanA gene is a useful marker for the detection of S. lugdunensis.

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