Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury.
Inhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury.
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DOI：
10.1016/j.jhep.2014.05.024
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发表时间：
2014-10
影响因子：
25.7
通讯作者：
Mandrekar, Pranoti
中科院分区：
文献类型：
--
作者：
Ambade, Aditya;Catalano, Donna;Lim, Arlene;Kopoyan, Andre;Shaffer, Scott A.;Mandrekar, Pranoti
热休克蛋白90（hsp 90）是慢性肝病治疗的新靶点。热休克蛋白90在肝脏免疫细胞活化中起重要作用，但其在酒精性肝病（ALD）中的作用仍不清楚。在此，我们假设热休克蛋白90在酒精诱导的脂肪变性和促炎细胞因子的产生中是至关重要的。为了验证这一假设，我们在急性和慢性酒精性肝损伤的体内小鼠模型中采用了hsp 90的药理学抑制剂17-DMAG [17-二甲基氨基-乙基氨基-17-去甲氧基格尔德霉素]。C57 BL/6小鼠经口灌胃给予单剂量乙醇（急性），或长期喂食乙醇2周，然后经口灌胃（慢性狂欢）。17-在喂食期间或喂食结束时给予DMAG。分析肝损伤指标、炎性细胞因子和脂代谢基因。我们的研究结果揭示了人类和小鼠酒精肝中hsp 90的表达增加。使用17-DMAG在体内抑制hsp 90不仅可以预防而且可以减轻酒精性肝损伤，这是通过降低血清ALT、AST和降低肝脏甘油三酯来确定的。机制分析表明，17-DMAG降低酒精介导的氧化应激，减少血清内毒素，减少炎性细胞，并减少肝巨噬细胞对LPS的敏感性，导致CD 14下调，NFκB抑制，并减少促炎细胞因子的产生。Hsp 90抑制通过减少核SREBP-1减少脂肪酸合成基因，并通过PPARα促进脂肪酸氧化基因。抑制热休克蛋白90降低酒精诱导的脂肪变性和促炎细胞因子，并抑制酒精性肝损伤。热休克蛋白90与酒精性肝硬化相关，是治疗酒精性肝硬化的有效靶点。
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. 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 analyzed. Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevents but also alleviates alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis shows that 17-DMAG decreases alcohol mediated oxidative stress, reduces serum endotoxin, decreases inflammatory cells, and diminishes sensitization of liver macrophages to LPS, resulting in down-regulation of CD14, NFκB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreases fatty acid synthesis genes via reduced nuclear SREBP-1 and favors fatty acid oxidation genes via PPARα. Inhibition of hsp90 decreases alcohol induced steatosis and pro-inflammatory cytokines and inhibits alcoholic liver injury. Hsp90 is relevant in human alcoholic cirrhosis and promising therapeutic target in ALD.
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酒精性肝病临床进展的当前实验观点。
DOI：
10.1111/j.1530-0277.2009.01015.x
发表时间：
2009-10
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Breitkopf K;Nagy LE;Beier JI;Mueller S;Weng H;Dooley S
通讯作者：
Dooley S
影响因子：
4.2
作者：
Frazier, Thomas H;Stocker, Abigail M;McClain, Craig J
通讯作者：
McClain, Craig J
影响因子：
2.7
作者：
Ohji, G;Hidayat, S;Yonezawa, K
通讯作者：
Yonezawa, K
影响因子：
3.3
作者：
Vega, VL;De Maio, A
通讯作者：
De Maio, A
DOI：
10.1111/j.1440-1746.2006.04650.x
发表时间：
2007-06-01
影响因子：
4.1
作者：
Thakur, Varsha;McMullen, Megan R.;Nagy, Laura E.
通讯作者：
Nagy, Laura E.