Farnesoid X receptor regulates forkhead Box O3a activation in ethanol-induced autophagy and hepatotoxicity

Redox Biol. 2014;2:991-1002. doi: 10.1016/j.redox.2014.08.007. Epub 2014 Aug 28.


Alcoholic liver disease encompasses a wide spectrum of pathogenesis including steatosis, fibrosis, cirrhosis, and alcoholic steatohepatitis. Autophagy is a lysosomal degradation process that degrades cellular proteins and damaged/excess organelles, and serves as a protective mechanism in response to various stresses. Acute alcohol treatment induces autophagy via FoxO3a-mediated autophagy gene expression and protects against alcohol-induced steatosis and liver injury in mice. Farnesoid X Receptor (FXR) is a nuclear receptor that regulates cellular bile acid homeostasis. In the present study, wild type and FXR knockout (KO) mice were treated with acute ethanol for 16h. We found that ethanol treated-FXR KO mice had exacerbated hepatotoxicity and steatosis compared to wild type mice. Furthermore, we found that ethanol treatment had decreased expression of various essential autophagy genes and several other FoxO3 target genes in FXR KO mice compared with wild type mice. Mechanistically, we did not find a direct interaction between FXR and FoxO3. Ethanol-treated FXR KO mice had increased Akt activation, increased phosphorylation of FoxO3 resulting in decreased FoxO3a nuclear retention and DNA binding. Furthermore, ethanol treatment induced hepatic mitochondrial spheroid formation in FXR KO mice but not in wild type mice, which may serve as a compensatory alternative pathway to remove ethanol-induced damaged mitochondria in FXR KO mice. These results suggest that lack of FXR impaired FoxO3a-mediated autophagy and in turn exacerbated alcohol-induced liver injury.

Keywords: Alcohol; Autophagy; Farnesoid X receptor; FoxO3a; Liver injury.

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Ethanol / toxicity*
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / metabolism*
  • Liver / metabolism*
  • Liver / pathology
  • Liver Diseases, Alcoholic / metabolism*
  • Liver Diseases, Alcoholic / pathology
  • Mice
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*


  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Ethanol