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

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 (Zfp36l1^flox/flox /Cre⁺; L1^LKO) mice. Under normal conditions, the L1^LKO mice and their littermate controls (Zfp36l1^flox/flox/Cre^-; L1^FLX) appeared normal. When fed a Lieber-DeCarli liquid diet containing alcohol, L1^LKO mice were significantly protected from developing alcohol-induced hepatic steatosis and inflammation compared to L1^FLX mice. Serum ALT levels were significantly increased in alcohol-fed L1^FLX versus alcohol-fed L1^LKO mice. RNA-Seq analysis revealed 584 differentially-expressed transcripts in L1^FLX alcohol-fed mice, many of which were inflammatory mediators, compared to only 159 in alcohol-fed L1^LKO mice. Most importantly, fibroblast growth factor 21 (Fgf21) mRNA was significantly increased in the livers of alcohol-fed L1^LKO 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.