Zhang W, Zhong W, Sun Q, Sun X, Zhou Z (2017) Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice. Scientific Reports 7(1):8976.
1. Center for Translational Biomedical Research, University of North Carolina Greensboro, North Carolina Research Campus, Kannapolis, NC, 28081, USA.
2. Center for Translational Biomedical Research, University of North Carolina Greensboro, North Carolina Research Campus, Kannapolis, NC, 28081, USA. firstname.lastname@example.org.
3. Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, 28081, USA. email@example.com.
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.