title: Inhibition of HMGB1 release via salvianolic acid B-mediated SIRT1 up-regulation protects rats against non-alcoholic fatty liver disease.
abstract: The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the regulation of HMGB1 in NAFLD, particularly through sirtuin 1 (SIRT1), remains unclear. In this study, we investigated the role of SIRT1-mediated inhibition of HMGB1 release in NAFLD and the effect of salvianolic acid B (SalB), which is a water-soluble phenolic acid extracted from Radix Salvia miltiorrhiza, on NAFLD through SIRT1/HMGB1 signaling. In vivo, SalB treatment significantly attenuated high-fat diet (HFD)-induced liver damage, hepatic steatosis, and inflammation. Importantly, SalB significantly inhibited HMGB1 nuclear translocation and release, accompanied by SIRT1 elevation. In HepG2 cells, palmitic acid (PA)-induced pro-inflammatory cytokines release were blocked by HMGB1 small interfering RNA (siRNA) transfection. Moreover, pharmacological SIRT1 inhibition by Ex527 induced HMGB1 translocation and release, whereas SIRT1 activation by resveratrol or SalB reversed this trend. SIRT1 siRNA abrogated the SalB-mediated inhibition of HMGB1 acetylation and release, suggesting that SalB-mediated protection occurs by SIRT1 targeting HMGB1 for deacetylation. We are the first to demonstrate that the SIRT1/HMGB1 pathway is a key therapeutic target for controlling NAFLD inflammation and that SalB confers protection against HFD- and PA-induced hepatic steatosis and inflammation through SIRT1-mediated HMGB1 deacetylation.
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Shan
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Pharmacy, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Zhenlu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, 116044, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yao
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D059305:Diet, High-Fat; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D019308:Palmitic Acid / Q000633:toxicity; D020011:Protective Agents / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D053630:Depsides
chemical_list: D001572:Benzofurans; D016207:Cytokines; D024243:HMGB1 Protein; D019308:Palmitic Acid; D020011:Protective Agents; D034741:RNA, Small Interfering; D000077185:Resveratrol; D056564:Sirtuin 1; D013267:Stilbenes; C076944:salvianolic acid B; D053630:Depsides