http://purl.uniprot.org/citations/29278707 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/29278707 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundChronic liver disease is becoming a major cause of morbidity and mortality worldwide. During liver injury, hepatic stellate cells (HSCs) trans-differentiate into activated myofibroblasts, which produce extracellular matrix. Succinate and succinate receptor (G-protein coupled receptor91, GPR91) signaling pathway has now emerged as a regulator of metabolic signaling. A previous study showed that succinate and its specific receptor, GPR91, are involved in the activation of HSCs and the overexpression of α-smooth muscle actin (α-SMA). Metformin, a well-known anti-diabetic drug, inhibits hepatic gluconeogenesis in the liver. Many studies have shown that metformin not only prevented, but also reversed, steatosis and inflammation in a nonalcoholic steatohepatitis (NASH) animal model. However, the role of metformin in HSC activation and succinate-GPR91 signaling has not been clarified.MethodsThe immortalized human HSCs, LX-2 cells, were used for the in vitro study. For the in vivo study, male C57BL/J6 mice were randomly divided into 3 groups and were fed with a methionine-choline-deficient diet (MCD diet group) as a nonalcoholic steatohepatitis (NASH) mouse model with or without 0.1% metformin for 12 weeks, or were fed a control methionine-choline-sufficient diet (MCS diet group).ResultsIn our study, metformin and 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), which is an analog of adenosine monophosphate, were shown to suppress α-SMA expression via enhanced phosphorylation of AMP-activated protein kinase (AMPK) and inhibition of succinate-GPR91 signaling in activated LX-2 cells induced by palmitate- or succinate. Metformin and AICAR also reduced succinate concentration in the cell lysates when LX-2 cells were treated with palmitate. Moreover, metformin and AICAR reduced interleukin-6 and, transforming growth factor-β1 production in succinate-treated LX-2 cells. Both metformin and AICAR inhibited succinate-stimulated HSC proliferation and cell migration. Mice fed a MCD diet demonstrated increased steatohepatitis and liver fibrosis compared to that of mice fed control diet. Metformin ameliorated steatohepatitis, liver fibrosis, inflammatory cytokine production and decreased α -SMA and GPR91expression in the livers of the MCD diet-fed mice.ConclusionThis study shows that metformin can attenuate activation of HSCs by activating the AMPK pathway and inhibiting the succinate-GPR91 pathway. Metformin has therapeutic potential for treating steatohepatitis and liver fibrosis."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.bbrc.2017.12.143"xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/author | "Park S.Y."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/author | "Park W.S."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/author | "Nguyen G."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/author | "Choi D.H."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/author | "Cho E.H."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/author | "Le C.T."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/date | "2018"xsd:gYear |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/name | "Biochem Biophys Res Commun"xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/pages | "2649-2656"xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/title | "Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition."xsd:string |
http://purl.uniprot.org/citations/29278707 | http://purl.uniprot.org/core/volume | "495"xsd:string |
http://purl.uniprot.org/citations/29278707 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/29278707 |
http://purl.uniprot.org/citations/29278707 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/29278707 |
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http://purl.uniprot.org/uniprot/#_Q9BXA5-mappedCitation-29278707 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29278707 |
http://purl.uniprot.org/uniprot/Q99MT6 | http://purl.uniprot.org/core/mappedCitation | http://purl.uniprot.org/citations/29278707 |
http://purl.uniprot.org/uniprot/Q9BXA5 | http://purl.uniprot.org/core/mappedCitation | http://purl.uniprot.org/citations/29278707 |