Regulation of peroxisome proliferator-activated receptor-γ in liver fibrosis
Regulation of peroxisome proliferator-activated receptor-γ in liver fibrosis
复制标题
DOI：
10.1152/ajpgi.00124.2006
复制
发表时间：
2006-11-01
影响因子：
4.5
通讯作者：
Rockey, Don C.
中科院分区：
文献类型：
--
作者：
Yang, Liu;Chan, Che-Chang;Rockey, Don C.
Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 291: G902-G911, 2006. First published June 22, 2006; doi:10.1152/ajpgi.00124.2006. - 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 gamma expression, we hypothesized that its expression is critical in stellate cell-mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo. PPAR gamma was depleted in rat livers by using an adenovirusCre recombinase system. PPAR gamma was overexpressed by using an additional adenoviral vector (AdPPAR gamma). Bile duct ligation was utilized to induce stellate cell activation and liver fibrosis in vivo; phenotypic effects (collagen I, smooth muscle alpha-actin, hydroxyproline content, etc.) were measured. PPAR gamma mRNA levels decreased fivefold and PPAR gamma 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 gamma 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 gamma overexpression resulted in significantly increased adiponectin mRNA expression and decreased collagen I and smooth muscle alpha-actin mRNA expression compared with controls. During in vivo fibrogenesis, rat livers exposed to AdPPAR gamma had significantly less fibrosis than controls. Collagen I and smooth muscle alpha-actin mRNA expression were significantly reduced in AdPPAR gamma-infected rats compared with controls (P < 0.05, n = 10). PPAR gamma-deficient mice exhibited enhanced fibrogenesis after liver injury, whereas PPAR gamma receptor overexpression in vivo attenuated stellate cell activation and fibrosis. The data highlight a critical role for PPAR gamma during in vivo fibrogenesis and emphasize the importance of the PPAR gamma pathway in stellate cells during liver injury.
