AhR-NQO1 Signaling in Hepatocytes Drives a Protective Response against Alcohol-induced NAD+ Depletion and Liver Damage

Alcohol-related liver disease (ALD) is one of the most prevalent forms of liver disease in the world. A better understanding of molecular mechanisms related to ALD is imperative toexplore therapeutic targets and improve liver health. Aryl hydrocarbon receptor (AhR) is a xenobiotic receptor that plays important role in hepatic detoxification response. However, the role of AhRin ALD remains unclear. In this work, we found that chronic alcohol consumption reduced AhR expression but induced AhRand NQO1 nuclear enrichment in hepatocytes of alcoholic hepatitis (AH) patients and ALD mice.AhRknockout exacerbated alcohol-induced liver injuryalong with reduction of NAD(P)H quinone dehydrogenase 1 (NQO1), indicating thatNQO1 expression is dependent on AhR.Interestingly, although NQO1 expression was dependent on AhR, NQO1 nuclear translocation was mediated by cellular NAD+/NADH ratio rather than AhR activation. Nuclear NQO1 supported NAD+-dependent enzymes function in ALD mice. NQO1 overexpression prevented alcohol-induced hepatic NAD+ depletion and reversed alcohol-induced liver injury. Pharmaceutical activation of AhR-NQO1 signaling by indole-3-carbinol (I3C) reversed alcohol-induced liver injury. In conclusion, our human and mouse studies demonstrate that AhR activation is a protective response to counteract alcohol-induced hepatic NAD+ depletion through induction of NQO1.The findings suggest that targeting the hepatic AhR-NQO1 pathway may serve as a novel therapeutic approach for ALD.