title: Identification of matrine as a promising novel drug for hepatic steatosis and glucose intolerance with HSP72 as an upstream target.
abstract: OBJECTIVE
  Matrine is a small molecule drug used in humans for the treatment of chronic viral infections and tumours in the liver with little adverse effects. The present study investigated its therapeutic efficacy for insulin resistance and hepatic steatosis in high-fat-fed mice.
  
  
  METHODS
  C57BL/J6 mice were fed a chow or high-fat diet for 10 weeks and then treated with matrine or metformin for 4 weeks. The effects on lipid metabolism and glucose tolerance were evaluated.
  
  
  RESULTS
  Our results first showed that matrine reduced glucose intolerance and plasma insulin level, hepatic triglyceride content and adiposity in high-fat-fed mice without affecting caloric intake. This reduction in hepatosteatosis was attributed to suppressed lipid synthesis and increased fatty acid oxidation. In contrast to metformin, matrine neither suppressed mitochondrial respiration nor activated AMPK in the liver. A computational docking simulation revealed HSP90, a negative regulator of HSP72, as a potential binding target of matrine. Consistent with the simulation results, matrine, but not metformin, increased the hepatic protein level of HSP72 and this effect was inversely correlated with both liver triglyceride level and glucose intolerance.
  
  
  CONCLUSIONS
  Taken together, these results indicate that matrine may be used for the treatment of type 2 diabetes and hepatic steatosis, and the molecular action of this hepatoprotective drug involves the activation of HSP72 in the liver.
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Xiao-Yi
authors.identifier: http://orcid.org/0000-0002-0102-0367
authors.initials: XY
authors.lastname: Zeng
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Xiu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Song-Pei
authors.initials: SP
authors.lastname: Li
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Ren
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Ruo-Qiong
authors.initials: RQ
authors.lastname: Sun
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Charlie C L
authors.initials: CC
authors.lastname: Xue
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hua-Liang
authors.initials: HL
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Hu
authors.affiliation: Lipid Biology and Metabolic Disease, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Vic, Australia.
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D016503:Drug Delivery Systems / Q000639:trends*; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000819:agonists* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011807:Quinolizines / Q000008:administration & dosage* / Q000378:metabolism; D000093842:Matrines
chemical_list: D000470:Alkaloids; D050884:HSP72 Heat-Shock Proteins; D011807:Quinolizines; D000093842:Matrines