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RNA Binding Protein ZFP36L1 Regulates Alcoholic Steatohepatitis in Mice
Author(s) -
Patial Sonika,
Saini Yogesh,
Bathula Chandra
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00482
Subject(s) - biology , steatohepatitis , steatosis , endocrinology , medicine , andrology , fatty liver , microbiology and biotechnology , disease
Zinc finger protein 36 like 1 (ZFP36L1) regulates mRNA levels by binding to AU‐rich elements (ARE’s) on the 3′untranslated regions (3′UTR) of specific mRNAs and enhancing their turnover. While the biochemical function of ZFP36L1 is somewhat understood, its physiological and pathological functions remain unknown. Here, we sought to investigate the roles of ZFP36L1 in liver physiology and pathology by generating liver‐specific deletion of ZFP36L1 (Zfp36l1 LKO ) using Cre‐loxP approach and subjecting them to alcoholic steatohepatitis. Liver‐specific loss of ZFP36L1 did not result in any aberrant phenotype in mice. However, Zfp36l1 LKO mice were significantly protected from developing alcohol‐induced hepatic steatosis in Lieber‐DeCarli liquid diet‐induced model of alcoholic steatohepatitis. Serum levels of ALT did not significantly increase in Zfp36l1 LKO mice upon alcohol consumption while serum levels of ALT were significantly upregulated in wild type (WT) alcohol‐treated mice. Transcriptomic analysis showed less than 170 differentially expressed transcripts in alcohol‐treated Zfp36l1 LKO mice compared to greater than 500 differentially expressed transcripts in alcohol‐treated WT mice. Mechanistically, the levels of fibroblast growth factor 21 (Fgf21) mRNA were significantly increased and lipoprotein lipase (Lpl) mRNA were significantly reduced in the livers of alcohol‐treated Zfp36l1 LKO mice compared to alcohol‐treated WT group. We further found evidence that Fgf21 mRNA is a direct target of ZFP36L1. FGF21 is a metabolic regulator of glucose and lipid metabolism and has been previously found to be significantly induced upon alcohol consumption and protect against alcohol‐induced liver injury. In summary, our results demonstrate that FGF21 is post‐transcriptionally regulated by ZFP36L1 in alcoholic liver injury. Modulation of levels of ZFP36L1 may be beneficial in the prevention or treatment of human alcoholic liver disease. Support or Funding Information Start Up Funds, LSUSVM