Elsevier

Molecular Metabolism

Volume 6, Issue 11, November 2017, Pages 1395-1406
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2017.08.004Get rights and content
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open access

Highlights

  • Binge ethanol consumption robustly increases circulating FGF21 levels in both humans and mice.

  • FGF21 does not play a role in ethanol clearance which is the same in WT and FGF21-KO mice.

  • In mice lacking FGF21, in two models of ethanol consumption there was either excess mortality or excess hepatic damage and inflammation.

  • These data suggest the FGF21 may have potential therapeutic value for alcoholic liver disease.

Abstract

Objective

Excess 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.

Methods

We 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).

Results

Acute 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.

Conclusions

Acute 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.

Keywords

Binge ethanol consumption
FGF21
Chronic ethanol consumption
Alcoholic liver disease

Abbreviations

ACSS2
acyl-coenzyme a synthetase short-chain family member 2
ADH 1 and 2
alcohol dehydrogenase 1 and 2
ALDH1α1
aldehyde dehydrogenase 1 alpha 1
ALD
alcoholic liver disease
ALT
alanine aminotransferase
CD68
cluster of differentiation 68
ChREBPβ
carbohydrate-responsive element-binding protein beta
CPT1α
carnitine palmitoyltransferase 1 alpha
CPT1β
carnitine palmitoyltransferase 1 beta
CYP2E1
cytochrome P450 family 2 subfamily E member 1
FAS
fatty acid synthase
FGF21
fibroblast growth factor 21
FGF21-KO
mice lacking the FGF21 gene
FGF21-OE
mice overexpressing the FGF21 gene
IP
intraperitoneal
LDC
Lieber–DeCarli diet
MCP1
monocyte chemoattractant protein 1
NAFLD
non-alcoholic fatty liver disease
PPARα
peroxisome proliferator-activated receptor alpha
SC
subcutaneous
SCD1
stearoyl-CoA desaturase 1
SEM
standard error of the mean
SREBP1c
sterol regulatory element-binding protein-1c
TNFα
tumor necrosis factor alpha
UCP2
uncoupling protein 2
WT
wild type

Cited by (0)

6

Present address: Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161 Rome, Italy.

7

Present address: 1Globe Health Institute, Norwood MA 02062, USA.

8

Present address: Alkermes Inc., Waltham MA 02451, USA.

9

Equally contributing authors.

10

Equally contributing senior authors.