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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. Liver-specific ZFP36L1-deficient (Zfp36l1 flox/flox /Cre + ; L1 LKO ) mice were generated to investigate the role of ZFP36L1 in liver physiology and pathology. 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, injury, and inflammation compared with L1 FLX mice. Most importantly, fibroblast growth factor 21 (Fgf21) mRNA was significantly increased in the livers of alcohol diet-fed L1 LKO mice compared with the alcohol diet-fed L1 FLX 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 wild-type ZFP36L1, but not by a non-binding zinc finger ZFP36L1 mutant. Finally, wild-type ZFP36L1, but not the ZFP36L1 mutant, bound to the Fgf21 3'UTR ARE RNA probe. These results demonstrate that ZFP36L1 inactivation protects against alcohol-induced hepatic steatosis and liver injury and inflammation, possibly by stabilizing Fgf21 mRNA. These findings suggest that the modulation of ZFP36L1 may be beneficial in the prevention or treatment of human alcoholic liver disease., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)