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Biomolecules 2015, 5(4), 2659-2674; doi:10.3390/biom5042659

Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity

1
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Natalia Osna and Kusum Kharbanda
Received: 7 May 2015 / Revised: 9 October 2015 / Accepted: 9 October 2015 / Published: 16 October 2015
(This article belongs to the Collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
View Full-Text   |   Download PDF [4218 KB, uploaded 16 October 2015]   |  

Abstract

Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. Wild type (WT), CYP2E1 knockout (KO) or CYP2E1 humanized transgenic knockin (KI), mice were fed an ethanol liquid diet or control dextrose diet for four weeks. In the last week, some mice received either saline or 3-methyladenine (3-MA), an inhibitor of autophagy, or rapamycin, which stimulates autophagy. Inhibition of autophagy by 3-MA potentiated the ethanol-induced increases in serum transaminase and triglyceride levels in the WT and KI mice but not KO mice, while rapamycin prevented the ethanol liver injury. Treatment with 3-MA enhanced the ethanol-induced fat accumulation in WT mice and caused necrosis in the KI mice; little or no effect was found in the ethanol-fed KO mice or any of the dextrose-fed mice. 3-MA treatment further lowered the ethanol-decrease in hepatic GSH levels and further increased formation of TBARS in WT and KI mice, whereas rapamycin blunted these effects of ethanol. Neither 3-MA nor rapamycin treatment affected CYP2E1 catalytic activity or content or the induction CYP2E1 by ethanol. The 3-MA treatment decreased levels of Beclin-1 and Atg 7 but increased levels of p62 in the ethanol-fed WT and KI mice whereas rapamycin had the opposite effects, validating inhibition and stimulation of autophagy, respectively. These results suggest that autophagy is protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. We speculate that autophagy-dependent processes such as mitophagy and lipophagy help to minimize ethanol-induced CYP2E1-dependent oxidative stress and therefore the subsequent liver injury and steatosis. Attempts to stimulate autophagy may be helpful in lowering ethanol and CYP2E1-dependent liver toxicity. View Full-Text
Keywords: chronic ethanol; cytochrome P450 2E1 (CYP2E1); autophagy protection; hepatotoxicity; oxidative stress; 3-methyladenine; rapamycin chronic ethanol; cytochrome P450 2E1 (CYP2E1); autophagy protection; hepatotoxicity; oxidative stress; 3-methyladenine; rapamycin
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lu, Y.; Cederbaum, A.I. Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity. Biomolecules 2015, 5, 2659-2674.

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