title: (S)YS-51, a novel isoquinoline alkaloid, attenuates obesity-associated non-alcoholic fatty liver disease in mice by suppressing lipogenesis, inflammation and coagulation.
abstract: Obesity-associated non-alcoholic fatty liver disease (NAFLD) increases coagulation and inflammation. We hypothesized that (S)YS-51, an agent found to be beneficial in animal models of sepsis, may reduce NAFLD in high-fat diet (HFD) mice by reducing coagulation and inflammation. C57BL/6 mice were fed either a chow diet or HFD and each was supplemented with or without (S)YS-51 (10mg/kg, daily, i.p.) for 16 weeks. The results showed that HFD caused significant increases in lipogenesis [CD36, fatty acid synthase (FAS) and sterol response element binding protein (SREBP)-1c mRNA and protein], inflammation [monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α, intercellular cell adhesion molecule-1 (ICAM-1), TGF-β, and procollagen type 1 mRNA, macrophage infiltration] and coagulation [tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) mRNA and thrombin antithrombin complex (TAT)] in the liver, adipose tissue and serum, which were significantly reduced by (S)YS-51. These results of (S)YS-51 were accompanied by significant reduction of weight gain, liver size, hepatic steatosis and fibrosis, blood cholesterol, hepatic triglyceride, and macrophage infiltration and inflammatory cytokines in adipose tissue without affecting food intake in HFD mice. Interestingly, (S)YS-51 increased SIRT1 mRNA and protein and AMPK expression in the liver of HFD mice by increasing both NAD(+)/NADH ratio and LKB1 phosphorylation. In HepG2 cells, (S)YS-51 activated SIRT1 followed by AMPK. Finally, (S)YS-51 improved glucose tolerance and insulin resistance in HFD mice. We concluded that (S)YS-51 attenuates NAFLD and insulin resistance in HFD mice by, at least, activation of SIRT1/AMPK signals. Thus, (S)YS-51 may be beneficial in NAFLD treatment.
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 PLUS program), Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 PLUS program), Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Chemistry, School of Natural Sciences, Sogang University, Seoul 121-742, Republic of Korea.
authors.forename: Se-Yun
authors.initials: SY
authors.lastname: Jang
authors.affiliation: Department of Chemistry, School of Natural Sciences, Sogang University, Seoul 121-742, Republic of Korea.
authors.forename: Moo Hyun
authors.initials: MH
authors.lastname: Oh
authors.affiliation: Department of Chemistry, School of Natural Sciences, Sogang University, Seoul 121-742, Republic of Korea. Electronic address: dhlee@sogang.ac.kr.
authors.forename: Duck-Hyung
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 PLUS program), Gyeongsang National University, Jinju 660-751, Republic of Korea. Electronic address: kcchang@gnu.kr.
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D059305:Diet, High-Fat / Q000009:adverse effects; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000150:complications; D007333:Insulin Resistance; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D009765:Obesity / Q000150:complications*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C495109:1-(beta-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetra-hydroisoquinoline; D044005:Tetrahydroisoquinolines; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: AMPK; Coagulation; High fat-diet; Inflammation; SIRT1