The Journal of pharmacy and pharmacology · 2018
Acanthoic acid suppresses lipin1/2 via TLR4 and IRAK4 signalling pathways in EtOH- and lipopolysaccharide-induced hepatic lipogenesis.
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Song Jian, Han Xin, Yao You-Li, Li Ya-Mei, Zhang Jing, Shao Dan-Yang, Hou Li-Shuang, Fan Ying, Song Shun-Zong, Lian Li-Hua, Nan Ji-Xing, Wu Yan-Ling
Аннотация
OBJECTIVES: In alcoholic liver disease, alcohol and lipopolysaccharide (LPS) are major stimulation factors of hepatic lipogenesis. Our objective was to determine the protective mechanism of acanthoic acid (AA) in EtOH- and LPS-induced hepatic lipogenesis.
METHODS: HSC-T6 cells were treated with ethanol (200 mm) plus LPS (1 μg/ml) for 1 h, followed by AA (10 or 20 μm) for another 6 h. C57BL/6 mice were pretreated with of AA (20 and 40 mg/kg) or equal volume of saline and then exposed to three doses of ethanol (5 g/kg body weight) within 24 h. The mice were sacrificed at 6 h after the last ethanol dosing.
KEY FINDINGS: Acanthoic acid significantly decreased the expressions of α-SMA, collagen-I, SREBP-1, and lipin1/2 induced, also decreased fat droplets caused by EtOH/LPS. AA treatment decreased the protein expressions of TLR4, CD14, IRAK4, TRAF3, p-TAK1 and NF-κB increased by EtOH/LPS on HSC cells. Results in vivo were consistent with results in vitro.
CONCLUSIONS: Our data demonstrated that AA might modulate hepatic fibrosis and lipid deposition in HSC-T6 cell stimulated with ethanol combined with LPS by decreasing lipin1/2 via TLR4 and IRAK4 signalling pathways, and AA might be considered as a potential therapeutic candidate for alcoholic liver disease.
METHODS: HSC-T6 cells were treated with ethanol (200 mm) plus LPS (1 μg/ml) for 1 h, followed by AA (10 or 20 μm) for another 6 h. C57BL/6 mice were pretreated with of AA (20 and 40 mg/kg) or equal volume of saline and then exposed to three doses of ethanol (5 g/kg body weight) within 24 h. The mice were sacrificed at 6 h after the last ethanol dosing.
KEY FINDINGS: Acanthoic acid significantly decreased the expressions of α-SMA, collagen-I, SREBP-1, and lipin1/2 induced, also decreased fat droplets caused by EtOH/LPS. AA treatment decreased the protein expressions of TLR4, CD14, IRAK4, TRAF3, p-TAK1 and NF-κB increased by EtOH/LPS on HSC cells. Results in vivo were consistent with results in vitro.
CONCLUSIONS: Our data demonstrated that AA might modulate hepatic fibrosis and lipid deposition in HSC-T6 cell stimulated with ethanol combined with LPS by decreasing lipin1/2 via TLR4 and IRAK4 signalling pathways, and AA might be considered as a potential therapeutic candidate for alcoholic liver disease.
Предметные рубрики MeSH
ActinsAnimalsCells, CulturedCollagenDiterpenesEthanolLipogenesisLipopolysaccharide ReceptorsLipopolysaccharidesLiverLiver Diseases, AlcoholicMAP Kinase Kinase KinasesMiceNF-kappa BPhosphatidate PhosphataseProtein Serine-Threonine KinasesRatsSignal TransductionSterol Regulatory Element Binding ProteinsTNF Receptor-Associated Factor 3Toll-Like Receptor 4MAP Kinase Kinase Kinase 7