Regulation of peroxisome proliferator-activated receptor-γ in liver fibrosis

Abstract

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