Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury

Background & Aims: 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 CD 14, NF kappa B 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 PPAR alpha. 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. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.