H4K12 Lactylation-activated c-JUN signaling aggravates bile acid dysfunction in intrahepatic cholestasis during pregnancy

The occurrence of hepatic cholestasis during pregnancy is accompanied by the disorders of glucose and lipid metabolism, especially the acceleration of glycolysis. Here, we reported a novel mechanism that the glycolysis metabolic intermediate lactate-induced histone 4 at K12 (H4K12) hyperlactylation aggravates bile acid (BA) dysfunction in intrahepatic cholestasis during pregnancy by activating c-JUN and in turn facilitating RXRɑ cytoplasmic relocalization. Lactylome analysis in livers of late pregnant sows with high levels of BA revealed induction of H4K12 hyperlactylation. Target correction of aberrant histone lactylation prevented the hepatic BA disorders in both sows and mice models. Mechanistically, H4K12la was enriched in promoter regions of c-JUN and activated its expression Moreover, activated c-JUN facilitated the RXRɑ phosphorylation and cytoplasmic relocalization, which resulted in the activation of whole BA synthesis pathway and inhibition of BA transport pathway. Inhibitor of the glycolysis pathway and lactate inhibitor as nutritional intervention ameliorated BA metabolic disorder in pregnant sows and cholestasis in mice. Our findings demonstrate the catalytic role of lactate on hepatic BA disorders in late pregnancy, we also provided a novel pattern of nutritional intervention to precisely target and regulate bile acid metabolism, and may open the new direction of nutritional epigenetic regulation of metabolic diseases. Liver samples from late gestation sows in high and normal bile acid groups were used to analyze target genes regulated by H4K12la