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 ␣1(I) and ␣-smooth muscle actin (␣-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-␥ (PPAR␥), SREBP1c, and CEBP␣ 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␥ agonist, strongly suppressed upregulation of collagen ␣1(I) and ␣-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␥ was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen ␣1(I) and ␣-SMA were significantly inhibited. We conclude that the PPAR␥ 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␥, suggesting the presence of PPAR␥-dependent as well as independent pathways in stellate cells.

Regulation of glucose and lipid homeostasis by adiponectin: Effects on hepatocytes, pancreatic β cells and adipocytes

“…However, upon activation, instead of adiponectin, HSCs switch to leptin production. Based on these observations, several studies have demonstrated the potential of using adiponectin for regression of fibrogenesis (71, 72). Shafiei et.al reported that adiponectin overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis.…”

“…Shafiei et.al reported that adiponectin overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis. In contrast, adiponectin knockout animals developed severe fibrosis (72). Summarizing these observations and adiponectin’s anti-apoptotic function, we hypothesize that adiponectin is anti-fibrotic agent by reinforcing HSCs to remain in the quiescent state to prevent activation and the release of pro-fibrotic and pro-inflammatory factors following the activation.…”

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

“…Another study demonstrated that, only in an adiponectinmediated manner, troglitazone suppressed upregulation of collagen 1(I) and SMA mRNA in HSCs isolated from wild-type mice [86].…”

The Role of PI3K p110gamma in chronic liver injury

“…These data indicate that despite elevated serum levels of adiponectin PI3K p110γ deficient mice cannot profit from the beneficial effects of adiponectin of hepatic lipid metabolism in fatty liver disease. However, adiponectin is known to additionally exhibit direct antifibrotic effects independently of its effects on hepatic lipid metabolism (Matsunami et al, 2010,Shafiei et al, 2011,Wanninger et al, 2011. Therefore, one may hypothesize that in the BDL model, where AdipoR1 expression is not affected by hepatic steatosis, PI3K p110γ deficient mice profit from elevated adiponectin levels, which may in part explain the differences observed between the two models.…”