Abstract
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.
Highlights
Excessive alcohol consumption has long been associated with the development of liver diseases, including steatosis, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma[1,2,3]
This study showed that 13-hydroxyoctadecadienoic acid (13-HODE) induced endoplasmic reticulum (ER) stress, perturbed lipid metabolism, and enhanced protein levels of Fas, cleaved Caspase 3 (c-CAS3), and c-PARP, leading to apoptosis and suggested that 13-HODE plays an important role in the pathogenesis of alcoholic liver disease (ALD)
ALOX15 has been shown to be linked with nonalcoholic fatty liver disease and high fat diet-induced steatohepatitis[18, 19], the present study suggests that ALOX15/13-HODE signaling promoted alcohol-induced hepatic steatosis, reactive oxygen species (ROS) production, ER stress, alteration of lipid metabolism, and apoptosis, and knockout of ALOX15 protected mice against alcohol-induced hepatic injury
Summary
Excessive alcohol consumption has long been associated with the development of liver diseases, including steatosis (fatty liver), hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma[1,2,3]. Fatty liver as the first stage of alcoholic liver disease (ALD) may not cause any symptoms, but generation of toxic lipid species at this stage plays critical role in the initiation and progression of ALD4. Chronic alcohol exposure disrupts lipid homeostasis in the liver through multiple lipid metabolic pathways, including de novo lipogenesis, fatty acid oxidation, lipid uptake, very low-density lipoprotein export, and detoxification[5,6,7,8]. Mechanistic studies showed that hepatic apoptosis could be triggered by a variety of signal pathways, including endoplasmic reticulum (ER) stress, cell death receptor-mediated signaling cascade, reactive oxygen species (ROS) generation, lysosomal permeabilization, and mitochondrial dysfunction[12,13,14,15,16]. Alcohol consumption induces oxidative stress and increases free fatty acid levels with linoleic acid being mostly elevated in the liver[5]. It has been shown that chronic alcohol feeding induces both lipid dyshomeostasis and hepatic apoptosis, the precise molecular mechanisms linking alcohol-induced lipid dyshomeostasis and hepatic apoptosis have not been fully defined
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