title: The Role of Lipin-1 in the Regulation of Fibrogenesis and TGF-β Signaling in Hepatic Stellate Cells.
abstract: 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.
authors.affiliation: *College of Pharmacy, Chosun University, Gwangju, 61452, Korea.
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Jang
authors.affiliation: *College of Pharmacy, Chosun University, Gwangju, 61452, Korea College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.
authors.forename: Kyu Min
authors.initials: KM
authors.lastname: Kim
authors.affiliation: *College of Pharmacy, Chosun University, Gwangju, 61452, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Yang
authors.affiliation: *College of Pharmacy, Chosun University, Gwangju, 61452, Korea.
authors.forename: Sam Seok
authors.initials: SS
authors.lastname: Cho
authors.affiliation: *College of Pharmacy, Chosun University, Gwangju, 61452, Korea.
authors.forename: Seung Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: *College of Pharmacy, Chosun University, Gwangju, 61452, Korea.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shin
authors.affiliation: MRC-GHF, College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Korea.
authors.forename: Il Je
authors.initials: IJ
authors.lastname: Cho
authors.affiliation: *College of Pharmacy, Chosun University, Gwangju, 61452, Korea shki@chosun.ac.kr.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
mesh_terms: D002461:Cell Line, Transformed; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000503:physiopathology*; D010711:Phosphatidate Phosphatase / Q000378:metabolism / Q000502:physiology*; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D013267:Stilbenes; D016212:Transforming Growth Factor beta; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase; D000077185:Resveratrol
keywords: Lipin-1; TGF-β; fibrogenesis.; hepatic stellate cells; resveratrol; ubiquitination