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

Am J Pathol. 2021 Nov 11:S0002-9440(21)00478-8. doi: 10.1016/j.ajpath.2021.10.017. Online ahead of print.ABSTRACTZinc 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, injury, and inflammation compared to L1FLX mice. Most importantly, fibroblast growth factor 21 (Fgf21) mRNA was significantly increased in the livers of alcohol-fed L1LKO mice compared to the alcohol-fed L1FLX 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 and inflammation, possibly ...
Source: The American Journal of Pathology - Category: Pathology Authors: Source Type: research