Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice

被引:346
作者
Lin, Chih-Wen [1 ,2 ,3 ]
Zhang, Hao [4 ]
Li, Min [4 ]
Xiong, Xiwen [5 ]
Chen, Xi [4 ]
Chen, Xiaoyun [4 ]
Dong, Xiaocheng C. [5 ]
Yin, Xiao-Ming [1 ,4 ,6 ]
机构
[1] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA
[2] I Shou Univ, Div Gastroenterol & Hepatol, Dept Med, E Da Hosp, Kaohsiung, Taiwan
[3] Kaohsiung Med Univ, Grad Inst Med, Sch Med, Kaohsiung, Taiwan
[4] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA
[5] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA
[6] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA
关键词
Macroautophagy; Hepatic steatosis; Alcohol; High fat diet; Carbamazepine; DISEASE; PROGRESSION; ACTIVATION; STRESS;
D O I
10.1016/j.jhep.2013.01.011
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury. Methods: C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. Results: In both acute and chronic ethanol condition, macroautophagy was activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo. Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non-alcoholic fatty liver condition. Conclusions: These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury. (c) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:993 / 999
页数:7
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