The Role of Lipin-1 in the Regulation of Fibrogenesis and TGF-β Signaling in Hepatic Stellate Cells.

The adipogenic transcriptional regulation was reported to inhibit transdifferentiation of hepatic stellate cells (HSCs), which constitute the main fibrogenic cell type in the liver. Lipin-1 exhibits a dual function: an enzyme that catalyzes the conversion of phosphatidate to diacylglycerol and a transcriptional regulator. However, the involvement of Lipin-1 in the regulation of transforming growth factor-β (TGF-β) signaling and fibrogenesis in HSCs is not fully understood. Here, we showed that Lipin-1 was downregulated in activated primary HSCs and TGF-β-treated LX-2 cells, immortalized human HSC cell lines. The downregulation of Lipin-1 by TGF-β was not dependent on altered mRNA stability but rather on protein stability. Treatment of LX-2 cells with the proteasome inhibitor led to the accumulation of Lipin-1. Moreover, we observed a significant increase in Lipin-1 polyubiquitination. Overexpression of Lipin-1 attenuated TGF-β-induced fibrogenic gene expression. In addition, Lipin-1 inhibited TGF-β-mediated activation of Sma and Mad-related family (SMAD), a major transcription factor that transduces intracellular signals from TGF-β. Resveratrol, a well-known natural polyphenolic antioxidant, is known to inhibit liver fibrosis, although its mechanism of action remains unknown. Our data showed that resveratrol significantly increased the levels of Lipin-1 protein and mRNA in HSCs. Further investigation revealed that resveratrol blocked the polyubiquitination of Lipin-1. Resveratrol inhibited TGF-β-induced fibrogenic gene expression. TGF-β-induced SMAD binding element-luciferase reporter activity was significantly diminished by resveratrol with a simultaneous decrease in SMAD3 phosphorylation. Consistently, knockdown of the Lipin-1 gene using siRNA abolished the inhibitory effect of resveratrol. We conclude that Lipin-1 can antagonize HSC activation through the inhibition of TGF-β/SMAD signaling and that resveratrol may affect Lipin-1 gene induction and contribute to the inhibition of TGF-β-mediated hepatic fibrogenesis.