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Hepatic CYP2B10 is highly induced by binge ethanol and contributes to acute-on-chronic alcohol-induced liver injury

ABSTRACT: We altered the NIAAA (Gao Binge Model) of 8 week chronic plus binge ethanol (E8G1) to have 3 total ethanol gavages (5 g/kg; 1 every 24h) of ethanol after 8 weeks of chronic ethanol feeding (E8G3) to determine how the liver responds to chronic plus consecutive binge ethanol. Surprisingly, E8G3 treatment induced lower levels of liver injury, steatosis, inflammation, and fibrosis as compared to mice after E8G1 treatment. Microarray analyses were performed, identifying several pathways that may contribute to the observed liver adaptation to binge ethanol. In addition, cytochrome P450 2B10 (Cyp2b10) was a top upregulated gene in the E8G1 group and further upregulated in the E8G3 group, but only moderately induced after chronic ethanol consumption, which was confirmed by RT-qPCR and western blot analyses. Genetic disruption of the Cyp2b10 gene worsened liver injury in E8G1 and E8G3 mice with higher blood ethanol levels compared to wild-type control mice, while in vitro experimentation revealed that CYP2b10 did not directly promote ethanol metabolism. Metabolomic analyses revealed significant differences in hepatic metabolites from E8G1-treated Cyp2b10 KO and WT mice, and these metabolic alterations may contribute to the reduced liver injury in Cyp2b10 KO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE212755 | GEO | 2022/09/07

REPOSITORIES: GEO

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Project description:Chronic and binge ethanol consumption in humans and in animal models has been associated with the induction of injury (such as fibrosis and scarring) in the liver as well as the intestine, brain, lung and immune system. The effects of chronic ethanol consumption on the human kidney are protective as seen in large population studies are controversial with the preponderance of the data suggesting protection less so than injury. The most recent meta-analysis was by Konig et al (2015) who studied 5476 participants aged 28–75 years from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study to assess associations between alcohol consumption and risk of chronic kidney disease (CKD). They found in this population-based cohort, alcohol consumption was inversely associated with the risk of developing CKD. The protective effects of ethanol on the kidney present a unique model system to develop new hypothesis on protection against end organ damage by fibrosis. The data on the effects of alcohol or alcohol consumption at the molecular level on renal parenchyma are sparse. In cell culture and animal models chronic ethanol exposure has been show to induce protein post-translational modification (acetylation), protein expression (upregulation of cytochrome P450 CYP2E1 and local platelet-activating factor receptor (PAFR) ligand formation) as well as neutrophil infiltration and activation. Since hepatocytes do not express PAFR, these data suggest that the response of the kidney to chronic alcohol consumption is distinct from that of the liver or lung. Therefore, we hypothesized that mechanisms of ethanol-induced renal injury or protection are regulated by a protein signaling networks (PSN) modulated acutely by the phosphoproteome and long term epigenetically by the acetylproteome. To address this hypothesis we have initiated a tiered proteomics study to determine the effects of chronic alcohol consumption on the murine kidney and with a secondary insult of acute exposure of lipopolysaccharide (LPS) on the renal proteome, phosphoproteome and the acetylproteome. Data have already been collected on the total proteome and the phosphoproteome using a multiplexing approach. Data will be collected early spring on the acetylproteome.

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Hepatic CYP2B10 is highly induced by binge ethanol and contributes to acute-on-chronic alcohol-induced liver injury

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