Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury

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.

Emerging roles of fibroblast growth factor 21 in critical disease

“…Both animal and population studies have provided insights into this field and demonstrated that FGF21 in circulation is elevated in several diseases and can be served as a potential biomarker (16)(17)(18)(19). FGF21 is also closely involved in the progression of acute-on-chronic liver failure (ACLF) and has a great predictive potential for organ failure (20)(21)(22). Hence, we aim to review and summarize the current status of FGF21 research in critical illness, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), acute myocardial injury (AMI), acute kidney injury (AKI), sepsis, and liver failure.…”

The crosstalk between fibroblast growth factor 21 (FGF21) system and substance use

“…Furthermore, alcohol intake or administration consistently increases endogenous FGF21 signaling, both in the blood as well as its hepatic expression, in animal models and humans. 11 , 34 , 46 , 47 , 48 , 49 , 50 These associations between alcohol and FGF21 suggest that endogenous increases in FGF21 following alcohol exposure promote homeostasis to counteract alcohol-induced biological changes.…”

“… 70 Several studies in humans and animal models point to a link between alcohol-associated liver damage and FGF21 levels, as well as a protective role for FGF21 in alcohol-induced liver damage, oxidative stress, and inflammation. 13 , 34 , 48 , 58 In general, experimental suppression of FGF21 signaling exacerbates the damaging effects of alcohol on the liver, whereas experimental augmentation of FGF21 signaling attenuates these effects.…”

Recent insights into the pathogenesis and therapeutic targets of chronic liver diseases

“…47 48 FGF21 has been reported to be increased in circulation and livers in both humans and mice with alcohol exposure. [49][50][51][52] FGF21-deficient mice exhibited exacerbated ALD and increased mortality with impaired lipolysis, increased lipogenesis and inflammation. 51 52 Recombinant FGF21 suppresses alcohol-induced hepatic steatosis and injury.…”