title: Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury.
abstract: OBJECTIVE
  Heat shock protein 90 (hsp90) is an emerging therapeutic target in chronic liver diseases. Hsp90 plays an important role in liver immune cell activation; however its role in alcoholic liver disease (ALD) remains elusive. Here we hypothesize that hsp90 is crucial in alcohol induced steatosis and pro-inflammatory cytokine production. To test this hypothesis, we employed a pharmacological inhibitor of hsp90, 17-DMAG (17-Dimethylamino-ethylamino-17-demethoxygeldanamycin) in an in vivo mouse model of acute and chronic alcoholic liver injury.
  
  
  METHODS
  C57BL/6 mice were given either a single dose of ethanol via oral gavage (acute) or chronically fed alcohol for 2 weeks followed by oral gavage (chronic-binge). 17-DMAG was administered during or at the end of feeding. Liver injury parameters, inflammatory cytokines and lipid metabolism genes were analysed.
  
  
  RESULTS
  Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevented but also alleviated alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis showed that 17-DMAG decreased alcohol mediated oxidative stress, reduced serum endotoxin, decreased inflammatory cells, and diminished sensitization of liver macrophages to LPS, resulting in downregulation of CD14, NFκB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreased fatty acid synthesis genes via reduced nuclear SREBP-1 and favoured fatty acid oxidation genes via PPARα.
  
  
  CONCLUSIONS
  Inhibition of hsp90 decreased alcohol induced steatosis and pro-inflammatory cytokines and inhibited alcoholic liver injury. Hsp90 is therefore relevant in human alcoholic cirrhosis and a promising therapeutic target in ALD.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, United States.
authors.forename: Aditya
authors.initials: A
authors.lastname: Ambade
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, United States.
authors.forename: Arlene
authors.initials: A
authors.lastname: Lim
authors.affiliation: Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, United States.
authors.forename: Andre
authors.initials: A
authors.lastname: Kopoyan
authors.affiliation: Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, United States. Electronic address: Pranoti.Mandrekar@umassmed.edu.
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000473:pathology; D008111:Liver Function Tests; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D016207:Cytokines; D005227:Fatty Acids; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
keywords: 17-DMAG; Alcoholic liver disease; Cellular stress; Ethanol; HSF1; Steatohepatitis; hsp90