Dataset Information

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

ABSTRACT:

Background

The chronic-plus-binge model of ethanol consumption, where chronically (8-week) ethanol-fed mice are gavaged a single dose of ethanol (E8G1), is known to induce steatohepatitis in mice. However, how chronically ethanol-fed mice respond to multiple binges of ethanol remains unknown.

Methods

We extended the E8G1 model to three gavages of ethanol (E8G3) spaced 24 h apart, sacrificed each group 9 h after the final gavage, analyzed liver injury, and examined gene expression changes using microarray analyses in each group to identify mechanisms contributing to liver responses to binge ethanol.

Results

Surprisingly, E8G3 treatment induced lower levels of liver injury, steatosis, inflammation, and fibrosis as compared to mice after E8G1 treatment. Microarray analyses identified several pathways that may contribute to the reduced liver injury after E8G3 treatment compared to E8G1 treatment. The gene encoding cytochrome P450 2B10 (Cyp2b10) was one of the top upregulated genes in the E8G1 group and was further upregulated in the E8G3 group, but only moderately induced after chronic ethanol consumption, as confirmed by RT-qPCR and western blot analyses. Genetic disruption of Cyp2b10 worsened liver injury in E8G1 and E8G3 mice with higher blood ethanol levels compared to wild-type control mice, while in vitro experiments revealed that CYP2b10 did not directly promote ethanol metabolism. Metabolomic analyses revealed significant differences in hepatic metabolites from E8G1-treated Cyp2b10 knockout and WT mice, and these metabolic alterations may contribute to the reduced liver injury in Cyp2b10 knockout mice.

Conclusion

Hepatic Cyp2b10 expression is highly induced after ethanol binge, and such upregulation reduces acute-on-chronic ethanol-induced liver injury via the indirect modification of ethanol metabolism.

SUBMITTER: Mackowiak B

PROVIDER: S-EPMC9771974 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Mackowiak Bryan B Xu Mingjiang M Lin Yuhong Y Guan Yukun Y Seo Wonhyo W Ren Ruixue R Feng Dechun D Jones Jace W JW Wang Hongbing H Gao Bin B

Alcoholism, clinical and experimental research 20221025 12

<h4>Background</h4>The chronic-plus-binge model of ethanol consumption, where chronically (8-week) ethanol-fed mice are gavaged a single dose of ethanol (E8G1), is known to induce steatohepatitis in mice. However, how chronically ethanol-fed mice respond to multiple binges of ethanol remains unknown.<h4>Methods</h4>We extended the E8G1 model to three gavages of ethanol (E8G3) spaced 24 h apart, sacrificed each group 9 h after the final gavage, analyzed liver injury, and examined gene expression ...[more]

PMID: 36224745

Similar Datasets

Project description:BackgroundAlcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are highly prevalent liver diseases that may coexist and contribute significantly to liver disease-related mortality. Obesity is a common underlying risk factor for both disorders. There has been little research investigating the combined effects of high fat diet (HFD) and alcohol. Current mouse models of alcohol- or fat-rich diet alone do not lead to severe liver injury. There is a need to develop animal models recapitulating human settings of drinking and diet to study the mechanisms of liver injury progression.MethodsC57BL6 male mice were fed either chow or HFD ad libitum for 12 weeks. A sub-set of mice from each group were also given alcohol (2 g kg(-)(1) body weight) twice a week via intra-gastric lavage. Animals were monitored progressively for weight gain and blood and livers were harvested at termination. The extent of liver injury was examined by histopathology as well as by liver and serum biochemistry. The expression of lipid metabolism, inflammation and fibrogenesis-related molecules was examined by quantitative reverse transcription PCR (Q-PCR) and immunofluorescence staining.ResultsHFD significantly increased total body weight, triglyceride and cholesterol, whereas alcohol increased liver weight. Alcohol+HFD in combination produced maximum hepatic steatosis, increased micro- and macro-vesicular lipid droplets, increased de novo lipogenesis (steroid response-element binding protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1)) and proliferation peroxisome activated receptor alpha (PPARα), and decreased fatty acid β-oxidation (Acyl-CoA oxidase 1 (ACOX1)). Alcohol+HFD treatment also increased the inflammation (CD45+, CD68+, F4/80+ cells; tumour necrosis factor-alpha (TNF-α), F4/80 mRNAs) and fibrogenesis (vimentin+ activated stellate cells, collagen 1 (Col1) production, transforming growth factor-beta (TGF-β) and Col-1 mRNAs) in mice livers.ConclusionsWe report a novel mouse model with more severe liver injury than either alcohol or HFD alone recapitulating the human setting of intermittent alcohol drinking and HFD.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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