Submitted on March 18, 2006
Accepted on June 1, 2006
Regulation of peroxisome proliferator-activated receptor 
(PPAR) in liver fibrosis
Liu Yang1, Che-Chang Chan1, Oh-Sang Kwon1, Songling Liu1, Jason McGhee1, Stephen Stimpson2, Lihong Chen2, W. Wallace Harrington3, William Symonds4, and Don C Rockey5*
1 Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina, United States
2 GlaxoSmithKline PLC, United States
3 GlaxoSmithKline PLC, Research Triangle Park, North Carolina, United States
4 Cell Biology and Medicine, Duke University Medical Center, United States
5 Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, United States
* To whom correspondence should be addressed. E-mail: don.rockey{at}utsouthwestern.edu.
INTRODUCTION:Peroxisome proliferator-activated receptors (PPARs) impart diverse cellular effects in biologic systems. Since stellate cell activation during liver injury is associated with declining PPAR
expression, we hypothesized its expression is critical in stellate cell mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo.
METHODS:PPAR was depleted in rat livers using an adenovirus/cre-recombinase system. PPAR was over expressed using an additional adenoviral vector (Ad.PPAR). Bile duct ligation (BDL) was utilized to induce stellate cell activation and liver fibrosis in vivo; phenotypic effects (collagen I, smooth muscle 
actin, hydroxyproline content, etc . . .) were measured.
RESULTS:PPAR mRNA levels decreased 5-fold 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 to controls (1.28mg/g liver tissue±0.14 versus 1.89mg/g±0.21, p<0.03). In isolated stellate cells, Ad.PPAR overexpression resulted in significantly increased adiponectin mRNA expression and decreased collagen I and smooth muscle actin mRNA expression compared to controls. During in vivo fibrogenesis, rat livers exposed to Ad.PPAR had significantly less fibrosis than controls. Collagen I and smooth muscle actin mRNA expression were significantly reduced in Ad.PPAR-infected rats compared to controls (p < 0.05, n = 10).
CONCLUSION:PPAR deficient mice exhibited enhanced fibrogenesis after liver injury, while 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.
