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[摘要]：In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing trans genic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin-null animals developed severe fibrosis. Expression of collagen alpha 1(I) and alpha-smooth muscle actin (alpha-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-gamma (PPAR gamma), SREBP1c, and CEBP alpha 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 PPAR gamma agonist, strongly suppressed upregulation of collagen alpha 1(I) and alpha-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 PPAR gamma was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen alpha 1(I) and alpha-SMA were significantly inhibited. We conclude that the PPAR gamma 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 PPAR gamma, suggesting the presence of PPAR gamma-dependent as well as independent pathways in stellate cells. (Am J Pathol 2011, 178:2690-2699; DOI: 10.1016/j.ajpath.2011.02.035) |
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