Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury

Abstract

ObjectiveExcess ethanol consumption has serious pathologic consequences. In humans, repeated episodes of binge drinking can lead to liver damage and have adverse effects on other organs such as pancreas and brain. Long term chronic consumption of ethanol can also result in progressive alcoholic liver disease and cirrhosis. Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple physiologic functions. FGF21 is a novel biomarker for non-alcoholic fatty liver disease (NAFLD) in humans and limits hepatotoxicity in mice. Therefore, we explored the possibility that FGF21 plays a role in response to ethanol consumption in both humans and mice.MethodsWe used a binge drinking paradigm in humans to examine the effect of acute ethanol consumption on circulating FGF21. We adapted this paradigm to evaluate the acute response to ethanol in mice. We then examined the role of FGF21 on liver pathology in two models of chronic ethanol consumption in both wild type (WT) mice and mice lacking FGF21 (FGF21-KO).ResultsAcute ethanol consumption resulted in a robust induction of serum FGF21 after 6 h in both humans and mice. Serum ethanol peaked at 1 h in both species and was cleared by 6 h. Ethanol clearance was the same in WT and FGF21-KO mice, indicating that FGF21 does not play a major role in ethanol metabolism in a binge paradigm. When FGF21-KO mice were fed the Lieber–DeCarli diet, a high fat diet supplemented with ethanol, a higher mortality was observed compared to WT mice after 16 days on the diet. When FGF21-KO mice consumed 30% ethanol in drinking water, along with a normal chow diet, there was no mortality observed even after 16 weeks, but the FGF21-KO mice had significant liver pathology compared to WT mice.ConclusionsAcute or binge ethanol consumption significantly increases circulating FGF21 levels in both humans and mice. However, FGF21 does not play a role in acute ethanol clearance. In contrast, chronic ethanol consumption in the absence of FGF21 is associated with significant liver pathology alone or in combination with excess mortality, depending on the type of diet consumed with ethanol. This suggests that FGF21 protects against long term ethanol induced hepatic damage and may attenuate progression of alcoholic liver disease. Further study is required to assess the therapeutic potential of FGF21 in the treatment of alcoholic liver disease.

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

“…It is the same variant that was previously associated with altered macronutrient consumption (rs838133-A) (Chu et al 2013;Tanaka et al 2013). Human studies have expanded on this association by challenging lean, healthy individuals with an alcohol bolus, which increased circulating FGF21 levels by as much as 40-fold after several hours (Desai et al 2017;Søberg et al 2018;Song et al 2018). In a natural setting featuring heavy voluntary alcohol intake, FGF21 levels were measured in subjects before and after participation in the Oktoberfest in Munich.…”

“…In addition to sugar consumption, FGF21 also regulates alcohol intake in mice. Transgenic mice overexpressing FGF21 demonstrate decreased preference for ethanol (Talukdar et al 2016;Desai et al 2017). A bi-specific antibody targeting the receptor complex (FGFR1c/KLB) has been developed, and testing in mice showed that both saccharin and alcohol consumption decreased thus suggesting that the antibody mimics the functions of the FGF21 hormone (Chen et al 2017).…”

“…; Desai et al . ). A bi‐specific antibody targeting the receptor complex (FGFR1c/KLB) has been developed, and testing in mice showed that both saccharin and alcohol consumption decreased thus suggesting that the antibody mimics the functions of the FGF21 hormone (Chen et al .…”

“…Further, FGF21 might exert a protective effect during sustained alcohol consumption, since FGF21‐KO mice exhibited more liver damage than WT mice after 16 weeks with 30% ethanol in their drinking water (Desai et al . ). FGF21 has also recently been implicated in contributing to alcohol‐induced thirst in mice (Song et al .…”

Fibroblast growth factor 21 in chronic kidney disease

“…Ethanol consumption robustly induces liver and serum FGF21 levels. With chronic ethanol consumption, FGF21 −/− mice had exaggerated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by sterol regulatory element-binding protein-1c (SREBP1c) and decreased expression of genes involved in fatty acid β-oxidation mediated by SIRT1/PGC1α and was reduced by rFGF21 treatment [79, 80]. …”