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LIVER AND BILIARY TRACT

Regulation of peroxisome proliferator-activated receptor- in liver fibrosis

¹Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina; ²GlaxoSmithKline, Research Triangle Park, North Carolina; and ³University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 18 March 2006 ; accepted in final form 1 June 2006

The peroxisome proliferator-activated receptors (PPARs) impart diverse cellular effects in biological systems. Because stellate cell activation during liver injury is associated with declining PPAR expression, we hypothesized that its expression is critical in stellate cell-mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo. PPAR was depleted in rat livers by using an adenovirus-Cre recombinase system. PPAR was overexpressed by using an additional adenoviral vector (AdPPAR). Bile duct ligation was utilized to induce stellate cell activation and liver fibrosis in vivo; phenotypic effects (collagen I, smooth muscle -actin, hydroxyproline content, etc.) were measured. PPAR mRNA levels decreased fivefold and PPAR protein was undetectable in stellate cells after culture-induced activation. During activation in vivo, collagen accumulation, assessed histomorphometrically and by hydroxyproline content, was significantly increased after PPAR depletion compared with controls (1.28 ± 0.14 vs. 1.89 ± 0.21 mg/g liver tissue, P < 0.03). In isolated stellate cells, AdPPAR overexpression resulted in significantly increased adiponectin mRNA expression and decreased collagen I and smooth muscle -actin mRNA expression compared with controls. During in vivo fibrogenesis, rat livers exposed to AdPPAR had significantly less fibrosis than controls. Collagen I and smooth muscle -actin mRNA expression were significantly reduced in AdPPAR-infected rats compared with controls (P < 0.05, n = 10). PPAR-deficient mice exhibited enhanced fibrogenesis after liver injury, whereas PPAR receptor overexpression in vivo attenuated stellate cell activation and fibrosis. The data highlight a critical role for PPAR during in vivo fibrogenesis and emphasize the importance of the PPAR pathway in stellate cells during liver injury.

stellate cell; cirrhosis; biliary; adenovirus; wound healing

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