Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice

• Published in: Scientific reports Vol. 7; no. 1; pp. 8976 - 10
• Main Authors: Zhang, Wenliang, Zhong, Wei, Sun, Qian, Sun, Xinguo, Zhou, Zhanxiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/2; 13/51; 631/45/287/1187; 631/80/304; 64/110; 64/60; 82/1; Acetaldehyde; Alcohol; Alcohols; Alcohols - toxicity; Animals; Apoptosis; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-lipoxygenase; Arachidonate 15-Lipoxygenase - metabolism; Cell death; Disease Models, Animal; Ethanol; Hepatocytes - drug effects; Hepatocytes - pathology; Humanities and Social Sciences; Linoleic acid; Linoleic Acids - biosynthesis; Lipid metabolism; Lipids; Lipoxygenase; Liver; Liver diseases; Liver Diseases, Alcoholic - physiopathology; Metabolic disorders; Metabolites; Mice; multidisciplinary; Oxidative stress; Rodents; Science; Science (multidisciplinary); Up-Regulation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02759-0

Chronic alcohol feeding causes lipid accumulation and apoptosis in the liver. This study investigated the role of bioactive lipid metabolites in alcohol-induced liver damage and tested the potential of targeting arachidonate 15-lipoxygenase (ALOX15) in treating alcoholic liver disease (ALD). Results showed that chronic alcohol exposure induced hepatocyte apoptosis in association with increased hepatic 13-HODE. Exposure of 13-HODE to Hepa-1c1c7 cells induced oxidative stress, ER stress and apoptosis. 13-HODE also perturbed proteins related to lipid metabolism. HODE-generating ALOX15 was up-regulated by chronic alcohol exposure. Linoleic acid, but not ethanol or acetaldehyde, induced ALOX15 expression in Hepa-1c1c7 cells. ALOX15 knockout prevented alcohol-induced liver damage via attenuation of oxidative stress, ER stress, lipid metabolic disorder, and cell death signaling. ALOX15 inhibitor (PD146176) treatment also significantly alleviated alcohol-induced oxidative stress, lipid accumulation and liver damage. These results demonstrated that activation of ALOX15/13-HODE circuit critically mediates the pathogenesis of ALD. This study suggests that ALOX15 is a potential molecular target for treatment of ALD.