Abstract
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 Abcb4−/− mice with deficiency of the hepatobiliary phospholipid transporter. Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4−/− (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 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 Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 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 Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr 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 Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr 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.
Highlights
Excessive alcohol consumption is associated with serious adverse effects in the liver, causing alcohol-associated liver disease (AALD) with a wide pathobiological and histopathological spectrum ranging from fat accumulation in hepatocytes to hepatocellular carcinoma (HCC) [1]
For the clinical validation of our findings from animal studies, we examined the effect of alcohol intake on FGF19, fibroblast growth factor 21 (FGF21), and bile acid metabolism in patients with alcoholassociated liver cirrhosis and healthy subjects as a control group
In line with our in vivo findings, these results suggest a direct role of exogenously administered FGF21 on Cyp7a1 gene suppression, which is independent of the farnesoid X receptor/small heterodimer partner (FXR/SHP) pathway
Summary
Excessive alcohol consumption is associated with serious adverse effects in the liver, causing alcohol-associated liver disease (AALD) with a wide pathobiological and histopathological spectrum ranging from fat accumulation in hepatocytes to hepatocellular carcinoma (HCC) [1]. With the modification of the LDC diet model such as chronic-plus-binge alcohol feeding, i.e., the NIAAA model of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Gao-binge model), higher aminotransferase levels, liver inflammation and steatosis, and even hepatic neutrophil infiltration mimicking the human condition could be established [8,9]. For better understanding of alcohol-induced acute inflammatory responses in chronically injured liver, we recently modeled alcohol-associated ACLI based on the chronic plus binge ethanol feeding model [8] in ATP binding cassette subfamily B member 4 knock out (Abcb4−/− ) mice, which resulted in exacerbated hepatic steatosis, liver injury, and inflammation [2]. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4−/− mice with deficiency of the hepatobiliary phospholipid transporter. Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro
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