title: Regulation of peroxisome proliferator-activated receptor-gamma 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 PPARgamma expression, we hypothesized that its expression is critical in stellate cell-mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo. PPARgamma was depleted in rat livers by using an adenovirus-Cre recombinase system. PPARgamma was overexpressed by using an additional adenoviral vector (AdPPARgamma). 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. PPARgamma mRNA levels decreased fivefold and PPARgamma 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 PPARgamma depletion compared with controls (1.28 +/- 0.14 vs. 1.89 +/- 0.21 mg/g liver tissue, P < 0.03). In isolated stellate cells, AdPPARgamma 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 AdPPARgamma had significantly less fibrosis than controls. Collagen I and smooth muscle alpha-actin mRNA expression were significantly reduced in AdPPARgamma-infected rats compared with controls (P < 0.05, n = 10). PPARgamma-deficient mice exhibited enhanced fibrogenesis after liver injury, whereas PPARgamma receptor overexpression in vivo attenuated stellate cell activation and fibrosis. The data highlight a critical role for PPARgamma during in vivo fibrogenesis and emphasize the importance of the PPARgamma pathway in stellate cells during liver injury.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Che-Chang
authors.initials: CC
authors.lastname: Chan
authors.forename: Oh-Sang
authors.initials: OS
authors.lastname: Kwon
authors.forename: Songling
authors.initials: S
authors.lastname: Liu
authors.forename: Jason
authors.initials: J
authors.lastname: McGhee
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stimpson
authors.forename: Lihong Z
authors.initials: LZ
authors.lastname: Chen
authors.forename: W Wallace
authors.initials: WW
authors.lastname: Harrington
authors.forename: William T
authors.initials: WT
authors.lastname: Symonds
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D002469:Cell Separation; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter / Q000235:genetics; D006909:Hydroxyproline / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D047495:PPAR gamma / Q000096:biosynthesis / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000963:Antimetabolites; D008024:Ligands; D047495:PPAR gamma; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D004247:DNA; D001973:Bromodeoxyuridine; D006909:Hydroxyproline