Physiological YAP activation alleviate ER stress to mitigate alcohol-induced liver damage by promoting ATF6 transcriptional activation

Alcohol-associated liver disease (ALD) is a major global health concern driven by chronic metabolic stress. Alcohol-induced ER stress is an early event in hepatocytes, which disrupts lipid metabolism and contributes to hepatic steatosis and inflammation, driving liver damage during the progression of ALD and other liver disorders. Here, we report that in a mouse chronic alcohol feeding model, YAP activity in the liver is reduced at early stages of alcohol exposure, primarily by ER stress-induced Unfolded Protein Response (UPR), independently of canonical Hippo kinase activities. We further found that YAP activity is reduced, with elevated ER stress in human ALD. We demonstrated that genetic deletion of Yap in hepatocytes exacerbates ALD, while overexpression or pharmacological activation of the wild-type (WT) YAP alleviates ALD and ER stress. The protective role of physiological YAP activation in reducing ER-stress-induced hepatic damage is further demonstrated by a substantial rescue of liver function and viability severely compromised by acetaminophen overdose. This is in sharp contrast to pathological YAP hyperactivation that occurs later in alcohol exposure, which exacerbates disease progression in alcoholic hepatitis (AH). Mechanistically, we show that transcriptional activation of Activating Transcription Factor 6 (ATF6), a key transmembrane ER stress sensor that also serves as a transcription factor after ER stress-induced cleavage. We found that ATF6 transcription activity is both necessary and sufficient to mediate the protective role of YAP in ER stress and alcohol induced liver injury, through its target genes Manf and Hspa5 (Grp78). YAP potentiates the ATF6 transcription activity in a TEAD-dependent manner. Our study identifies an ATF6-dependent protective role of YAP in maintaining ER homeostasis, which can be leveraged to prevent or treat ALD and other liver diseases.