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Transcriptomic Profiling Identifies Novel Hepatic and Intestinal Genes Following Chronic Plus Binge Ethanol Feeding in Mice

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Abstract

Background

Alcohol-associated liver disease accounts for half of cirrhosis-related deaths worldwide. The spectrum of disease varies from simple steatosis to fibrosis, cirrhosis and ultimately hepatocellular carcinoma. Understanding the disease on a molecular level helps us to develop therapeutic targets.

Aim

We performed transcriptomic analysis in liver and ileum from chronic plus binge ethanol-fed mice, and we assessed the role of selected differentially expressed genes and their association with serum bile acids and gut microbiota.

Methods

Wild-type mice were subjected to a chronic Lieber-DeCarli diet model for 8 weeks followed by one binge of ethanol. RNA-seq analysis was performed on liver and ileum samples. Associations between selected differentially regulated genes and serum bile acid profile or fecal bacterial profiling (16S rDNA sequencing) were investigated.

Results

We provide a comprehensive transcriptomic analysis to identify differentially expressed genes, KEGG pathways, and gene ontology functions in liver and ileum from chronic plus binge ethanol-fed mice. In liver, we identified solute carrier organic anion transporter family, member 1a1 (Slco1a1; encoding for organic anion transporting polypeptides (OATP) 1A1), as the most down-regulated mRNA, and it is negatively correlated with serum cholic acid level. Prokineticin 2 (Prok2) mRNA, a cytokine-like molecule associated with gastrointestinal tract inflammation, was significantly down-regulated in ethanol-fed mice. Prok2 mRNA expression was negatively correlated with abundance of Allobaculum (genus), Coprococcus (genus), Lachnospiraceae (family), Lactococcus (genus), and Cobriobacteriaceae (family), while it positively correlated with Bacteroides (genus).

Conclusions

RNA-seq analysis revealed unique transcriptomic signatures in the liver and intestine following chronic plus binge ethanol feeding.

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Abbreviations

DEG:

Differentially expressed gene

GO:

Gene ontology

Slco1a1 :

Solute carrier organic anion transporter family, member 1a1

OATP:

Organic anion transporting polypeptides

NTCP:

Sodium-dependent taurocholate cotransporting polypeptide

TNF:

Tumor necrosis factor

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Acknowledgments

This study was supported in part by NIH Grants R01 AA24726, R01 AA020703, U01 AA026939, by Award Number BX004594 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.). The study was also supported by the NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515) and by the NIAAA-funded Southern California Research Center for ALPD and Cirrhosis (P50 AA011999).

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Authors and Affiliations

  1. Department of Medicine, University of California San Diego, MC0063, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Lu Jiang, Huikuan Chu, Bei Gao, Sonja Lang, Yanhan Wang, Yi Duan & Bernd Schnabl

  2. Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA

    Lu Jiang, Yanhan Wang, Yi Duan & Bernd Schnabl

  3. Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Huikuan Chu

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  1. Lu Jiang
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Contributions

LJ was responsible for acquisition, analysis and interpretation of data, and writing of the manuscript; HC performed mouse studies; BG and SL provided assistance in data analysis; YD and YW provided assistance in data acquisition; BS was responsible for the study concept and design, critical revision of the manuscript, and study supervision.

Corresponding author

Correspondence to Bernd Schnabl.

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Conflict of interest

B.S. has been consulting for Ferring Research Institute, Intercept Pharmaceuticals, HOST Therabiomics and Patara Pharmaceuticals. B.S.’s institution UC San Diego has received Grant support from BiomX, NGM Biopharmaceuticals, CymaBay Therapeutics, Synlogic Operating Company and Axial Biotherapeutics.

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Jiang, L., Chu, H., Gao, B. et al. Transcriptomic Profiling Identifies Novel Hepatic and Intestinal Genes Following Chronic Plus Binge Ethanol Feeding in Mice. Dig Dis Sci 65, 3592–3604 (2020). https://doi.org/10.1007/s10620-020-06461-6

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  • DOI: https://doi.org/10.1007/s10620-020-06461-6

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