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.
Highlights
Over the last decade, fibroblast growth factor 21 (FGF21) has emerged as a critical metabolic regulator
The peak in FGF21 was proportional to the amount of ethanol consumed (Figure 1A) as subjects receiving 0.4 g/kg ethanol peaked at 700 Æ 348 pg/ml (P 1⁄4 0.03), while subjects receiving 0.9 g/kg ethanol peaked at 2194 Æ 328 pg/ml (P < 0.0001)
FGF21 can be induced in inguinal fat depots upon cold exposure [22] and in muscle that is under stress induced by a mitochondrial myopathy [26]
Summary
Fibroblast growth factor 21 (FGF21) has emerged as a critical metabolic regulator. Two studies examining longer term fasting in women for 7 and 10 days report increased FGF21 levels. As this is accompanied by higher levels of hepatic transaminases, this rise may represent a stress response [5]. In contrast to the discordant responses between mice and humans to fasting and ketogenic diets, hepatic fat accumulation leads to a consistent increase in FGF21 hepatic gene expression and a 3e4 fold increase in circulating levels, reported in both humans and mice [4,6,7]. In lean healthy humans and in individuals with metabolic syndrome, acute oral loading of fructose leads to a robust increase in circulating FGF21 within 2 h, which declines over the ensuing 5e6 h [8]. FGF21 is elevated after an acute gavage of fructose and after fasting-refeeding with a high fructose diet; this increase appears to be mediated by the transcription factor
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