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ZFP36L1 regulates Fgf21 mRNA turnover and modulates alcoholic hepatic steatosis and inflammation in mice

Chandra S. Bathula, Jian Chen, Perry J. Blackshear, View ORCID ProfileYogesh Saini, View ORCID ProfileSonika Patial
doi: https://doi.org/10.1101/2021.05.11.443631
Chandra S. Bathula
1Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803
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Jian Chen
1Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803
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Perry J. Blackshear
2Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
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Yogesh Saini
1Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803
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Sonika Patial
1Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803
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  • For correspondence: spatial@lsu.edu
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ABSTRACT

Zinc finger protein 36 like 1 (ZFP36L1) enhances the turnover of mRNAs containing AU-rich elements (AREs) in their 3’untranslated regions (3’UTR). The physiological and pathological functions of ZFP36L1 in liver, however, remain largely unknown. To investigate the role of ZFP36L1 in liver physiology and pathology, we generated liver-specific ZFP36L1-deficient (Zfp36l1flox/flox /Cre+; L1LKO) mice. Under normal conditions, the L1LKO mice and their littermate controls (Zfp36l1flox/flox/Cre-; L1FLX) appeared normal. When fed a Lieber-DeCarli liquid diet containing alcohol, L1LKO mice were significantly protected from developing alcohol-induced hepatic steatosis and inflammation compared to L1FLX mice. Serum ALT levels were significantly increased in alcohol-fed L1FLX versus alcohol-fed L1LKO mice. RNA-Seq analysis revealed 584 differentially-expressed transcripts in L1FLX alcohol-fed mice, many of which were inflammatory mediators, compared to only 159 in alcohol-fed L1LKO mice. Most importantly, fibroblast growth factor 21 (Fgf21) mRNA was significantly increased in the livers of alcohol-fed L1LKO mice but not in the alcohol-fed control group. The Fgf21 mRNA contains three AREs in its 3’UTR, and Fgf21 3’UTR was directly regulated by ZFP36L1 in luciferase reporter assays. Steady state levels of Fgf21 mRNA were significantly decreased by wildtype ZFP36L1, but not by a non-binding zinc-finger ZFP36L1 mutant. Finally, wildtype ZFP36L1, but not the ZFP36L1 mutant, bound to Fgf21 3’UTR ARE RNA probe. Our results demonstrate that ZFP36L1 inactivation protects against alcohol-induced hepatic steatosis and liver injury, possibly by stabilizing Fgf21 mRNA. Our findings suggest that the modulation of ZFP36L1 may be beneficial in the prevention or treatment of human alcoholic liver disease.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding: The work was supported by LSU COBRE (NIGMS Grant # 5P30GM110760 and # P20GM130555) and LSU SVM Startup funds (SP). It was also supported in part by the Intramural Research Program of the NIEHS, a component of the National Institutes of Health (PJB).

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 11, 2021.
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ZFP36L1 regulates Fgf21 mRNA turnover and modulates alcoholic hepatic steatosis and inflammation in mice
Chandra S. Bathula, Jian Chen, Perry J. Blackshear, Yogesh Saini, Sonika Patial
bioRxiv 2021.05.11.443631; doi: https://doi.org/10.1101/2021.05.11.443631
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ZFP36L1 regulates Fgf21 mRNA turnover and modulates alcoholic hepatic steatosis and inflammation in mice
Chandra S. Bathula, Jian Chen, Perry J. Blackshear, Yogesh Saini, Sonika Patial
bioRxiv 2021.05.11.443631; doi: https://doi.org/10.1101/2021.05.11.443631

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