Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury

Abstract

Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates glucose and lipid metabolism in the liver. We sought to determine the role of FGF21 in hepatic steatosis in mice exposed to chronic alcohol treatment and to discern underlying mechanisms. Male FGF21 knockout (FGF21 KO) and control (WT) mice were divided into groups that were fed either the Lieber DeCarli diet containing 5% alcohol or an isocaloric (control) diet for 4 weeks. One group of WT mice exposed to alcohol received recombinant human FGF21 (rhFGF21) in the last 5 days. Liver steatosis and inflammation were assessed. Primary mouse hepatocytes and AML-12 cells were incubated with metformin or rhFGF21. Hepatic genes and the products involved in in situ lipogenesis and fatty acid β-oxidation were analyzed. Alcohol exposure increased circulating levels and hepatic expression of FGF21. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid β-oxidation mediated by PGC1α. rhFGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. These results reveal that alcohol-induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. Targeting FGF21 signaling could be a novel treatment approach for alcoholic steatohepatitis.

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

“…The detrimental roles of highly elevated FGF21 in the chronic-plus-binge ethanol-induced liver injury are likely due to FGF21-mediated induction of systemic catecholamines, which promote adipose tissue lipolysis and subsequently induce lipotoxicity in the liver 76 . The protective functions of FGF21 in chronically ethanol-fed mice were due to FGF-induced inhibition of the expression of genes associated with lipogenesis and stimulation of those associated with oxidation in the liver 75 .…”

“…For example, fibroblast growth factor 21 (FGF21) is an FGF family member that is produced by the liver and other metabolic tissues and plays an important role in regulating glucose and lipid metabolism 72–74 . Recent studies reported that chronic-plus-binge ethanol feeding or chronic ethanol feeding markedly upregulates FGF21 levels in the liver and serum, with much higher levels in chronic-plus-binge ethanol-fed groups than in chronically ethanol-fed mice 75, 76 . Interestingly, FGF21 knockout mice were protected from chronic-plus-binge ethanol-induced liver injury but were more susceptible to chronic ethanol feeding-induced hepatotoxicity 75 .…”

“…Recent studies reported that chronic-plus-binge ethanol feeding or chronic ethanol feeding markedly upregulates FGF21 levels in the liver and serum, with much higher levels in chronic-plus-binge ethanol-fed groups than in chronically ethanol-fed mice 75, 76 . Interestingly, FGF21 knockout mice were protected from chronic-plus-binge ethanol-induced liver injury but were more susceptible to chronic ethanol feeding-induced hepatotoxicity 75 . The detrimental roles of highly elevated FGF21 in the chronic-plus-binge ethanol-induced liver injury are likely due to FGF21-mediated induction of systemic catecholamines, which promote adipose tissue lipolysis and subsequently induce lipotoxicity in the liver 76 .…”

Adipose tissue autophagy and homeostasis in alcohol-induced liver injury

“…However, these two different alcohol models led to different outcomes for liver injury in FGF21 knockout mice [104, 129]. Gao-binge alcohol-induced liver injury and steatosis were attenuated in FGF21 knockout mice.…”

“…Mechanistically, the authors did not observe any changes in insulin levels, but catecholamine levels decreased in FGF21 knockout mice [104]. Regardless of these controversial findings in chronic or Gao-binge alcohol-treated FGF21 knockout mice, recombinant FGF21 treatment ameliorates alcohol-induced liver injury and steatosis [129, 130]. Whether FGF21 also affects autophagy in adipose tissue, thereby affecting ALD pathogenesis, remains unanswered and is currently under active investigation in our laboratory.…”