title: Betulin alleviated ethanol-induced alcoholic liver injury via SIRT1/AMPK signaling pathway.
abstract: The present study was conducted to investigate the protective effect of betulin, a triterpene from the bark of Betula platyphylla Suk, against ethanol-induced alcoholic liver injury and its possible underlying mechanisms. In vitro, human hepatic stellate cell line, LX-2 cells were treated with betulin (6.25, 12.5 and 25 μM) prior to ethanol (50mM) for 24h. Cell viability was analyzed by methyl thiazolyl tetrazolium assay, protein expressions were assessed by Western blot. In vivo, we induced alcoholic liver injury in male C57BL/6 mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Betulin (20 and 50mg/kg) were given by gavage every day. In vitro results showed that betulin effectively decreased LX-2 cell viability, attenuated collagen-I, α-smooth muscle actin (α-SMA) levels, activated liver kinase B-1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Betulin suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1), and genetic deletion of AMPK blocked the effect of betulin on SREBP-1 in ethanol treated LX-2 cells. In vivo, betulin attenuated the increases in serum aminotransferase and triglyceride levels in the mice fed with chronic-binge ethanol, while significantly inhibited SREBP-1 expression and activated LKB1-AMPK phosphorylation. Additionally, betulin enhanced the sirtuin 1 (SIRT1) expression mediated by ethanol. Taken together, betulin alleviates alcoholic liver injury possibly through blocking the regulation of SREBP-1 on fatty acid synthesis and activating SIRT1-LKB1-AMPK signaling pathway.
authors.affiliation: Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; College of School of Biological Science and Technology, Jinan University, Jinan 250022, Shandong Province, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Bai
authors.affiliation: Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: You-Li
authors.initials: YL
authors.lastname: Yao
authors.affiliation: Clinical Research Center, Yanbian University Hospital, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Lian
authors.affiliation: Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: ylwu@ybu.edu.cn.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Clinical Research Center, Yanbian University Hospital, China. Electronic address: jxnan@ybu.edu.cn.
authors.forename: Ji-Xing
authors.initials: JX
authors.lastname: Nan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D029662:Betula / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014315:Triterpenes / Q000627:therapeutic use*; D000094062:Betulinic Acid
chemical_list: D055372:AMP-Activated Protein Kinases; D000431:Ethanol; D056564:Sirtuin 1; D051780:Sterol Regulatory Element Binding Protein 1; D014315:Triterpenes; C002503:betulin; D000094062:Betulinic Acid
keywords: AICAR (PubChem CID: 266934); AMPK; Alcoholic liver injury; Betulin; Betulin (PubChem CID: 72326); Dimethyl sulfoxide (PubChem CID: 679); Ethanol (PubChem CID: 702); LKB1; Methylthiazolyltetrazolium (PubChem CID: 64965); PDTC (PubChem CID: 46780289); SIRT1