Association of fibroblast growth factor 21 with alcohol consumption and alcohol liver cirrhosis

Abstract

Summary Background Fibroblast growth factor 21 (FGF21) is produced in the liver and binds to different complex receptor/coreceptor systems. Besides many other processes, FGF21 regulates the intake of simple sugars and alcohol. Increased levels of FGF21 decrease harmful alcohol intake in mice. To increase our understanding on the relationship between FGF21 and alcohol intake in humans, we aimed to measure FGF21 levels in patients with alcoholic liver cirrhosis (ALC) in comparison to patients with nonalcoholic liver cirrhosis (NALC) and healthy persons based on their present alcohol consumption. Methods Alcohol intake was verified by urinary ethyl glucuronide (uETG) levels, eating and drinking behaviour by a Food Frequency Questionnaire and FGF 21 plasma levels were determined by ELISA in 96 persons (ALC n = 41; NALC n = 34; healthy n = 21). Results Both ALC and NALC patients with elevated ETG levels (≥0.5 μg/ml; indicating alcohol consumption in the last 12–72 h) showed significantly higher FGF21 plasma levels in comparison to patients with negative ETG levels. Eating behaviour did not have an impact on FGF21 plasma levels. Conclusions Increased FGF21 levels in patients with recent alcohol consumption (verified by ETG) confirmed the first part of the liver–brain endocrine axis: alcohol consumption was associated with increased FGF21 levels. We could not confirm that elevated FGF21 levels were associated with reduced alcohol intake as a result. That points towards a pathology in this pathway, which might be caused by a malfunction of β‑Klotho or FGF receptors according to other studies and chronic alcohol dependency. Further research is required to clarify these pathologies, which may open new pharmacological treatment for patients with alcohol use disorder and alcohol dependence.

FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit

“…Endogenous FGF21 and pharmacologic administration of FGF21 suppress alcohol consumption in rodents and non-human primates Both chronic alcohol consumption and acute binge-like consumption increase circulating levels of endogenous FGF21 (Desai et al, 2017;Liu et al, 2016;Søberg et al, 2018;Wagner-Skacel et al, 2021). To determine if circulating FGF21 induced by ethanol consumption is derived from the liver, as is the case for many nutritional challenges (Flippo and Potthoff, 2021), we deleted FGF21 in the liver by administering AAV viruses expressing either Cre recombinase or a control construct under a liver-specific promoter (AAV-TBG-Cre and AAV-TBG-Con, respectively) to mice harboring a floxed FGF21 allele (FGF21 fl/fl ) (Figures S1A and S1B).…”

“…suppresses alcohol consumption by enhancing the excitability of a specific subpopulation of these neurons. The association of increased FGF21 levels with alcohol consumption and alcohol liver cirrhosis (Wagner-Skacel et al, 2021) may suggest that a pathology in this pathway contributes to alcohol dependency. Importantly, FGF21 and the FGF21 analog PF-05231023 effectively function to decrease alcohol intake even when administered after prolonged ethanol exposure in mice and primates.…”

FGF21 regulates alcohol intake: New hopes on the rise for alcohol use disorder treatment?

“… 3 Both preclinical and clinical studies recently found that alcohol consumption increases endogenous FGF21 levels. 4 , 5 Albeit preliminary, these findings suggest that elevated FGF21 following alcohol use may lead to reduced alcohol intake, potentially through acting on the co-receptor β-klotho (encoded by the KLB gene) expressed in the brain. 5 Therefore, it is possible to hypothesize that a liver-brain axis pathway like FGF21 may serve as a viable target for AUD treatment.…”

“… 4 , 5 Albeit preliminary, these findings suggest that elevated FGF21 following alcohol use may lead to reduced alcohol intake, potentially through acting on the co-receptor β-klotho (encoded by the KLB gene) expressed in the brain. 5 Therefore, it is possible to hypothesize that a liver-brain axis pathway like FGF21 may serve as a viable target for AUD treatment. However, little work to date has investigated neural mechanisms underlying FGF21’s interplay with alcohol consumption as well as its effects in higher order mammals.…”

Oxidative stress-induced growth inhibitor 1 in alcohol-induced liver cirrhosis

“…Yang et al investigated serum levels of FGF-21 in diagnosing nonalcoholic steatoheaptitis (NASH) and the critical stage of non-alcoholic fatty liver disease (NAFLD) [19]. In a recent study, Wagner-Skacel et al showed that increased FGF21 levels in patients correlated with recent alcohol consumption [20]. Remmler et al indicated that the serum level of IL-6 and Model of End-Stage Liver Disease (MELD) scores are associated with mortality in patients with end-stage liver disease, evaluated for liver transplantation [21].…”