title: Adiponectin regulation of stellate cell activation via PPARγ-dependent and -independent mechanisms.
abstract: In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin-null animals developed severe fibrosis. Expression of collagen α1(I) and α-smooth muscle actin (α-SMA) mRNAs were significantly lower in adiponectin-overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator-activated receptor-γ (PPARγ), SREBP1c, and CEBPα mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n = 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPARγ agonist, strongly suppressed up-regulation of collagen α1(I) and α-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPARγ was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen α1(I) and α-SMA were significantly inhibited. We conclude that the PPARγ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPARγ, suggesting the presence of PPARγ-dependent as well as independent pathways in stellate cells.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Mahnoush S
authors.initials: MS
authors.lastname: Shafiei
authors.forename: Shoba
authors.initials: S
authors.lastname: Shetty
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
mesh_terms: D052242:Adiponectin / Q000172:deficiency / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight; D004198:Disease Susceptibility; D017353:Gene Deletion; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000378:metabolism*; D010641:Phenotype; D013853:Thioacetamide
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D008024:Ligands; D047495:PPAR gamma; D013853:Thioacetamide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase