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Background and Aims: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in <i>Abcb4^−/−</i> mice with deficiency of the hepatobiliary phospholipid transporter. Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and <i>Abcb4⁻/⁻</i> (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; <i>n</i> = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; <i>n</i> = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; <i>n</i> = 31) and healthy controls (<i>n</i> = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic <i>Cyp7a1</i> levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (<i>Fgfr1</i>), <i>Fgfr4</i>, Farnesoid X-activated receptor (<i>Fxr</i>), and Small heterodimer partner (<i>Shp</i>) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed <i>Cyp7a1</i> in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. Conclusions: The simultaneous upregulation of FGF21 and downregulation of <i>Cyp7a1</i> expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic <i>Shp</i> and <i>Fxr</i> levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of <i>Cyp7a1</i> expressions while circulating FGF15 and hepatic <i>Shp</i> and <i>Fxr</i> levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1.