Hepatic CBP/p300 maintain bile acid homeostasis through histone acetylation-mediated KLF10-BSEP axis

BACKGROUND & AIMS: Disruption of bile acid metabolism contributes to various liver diseases. Although CBP/p300 are known regulators of hepatic metabolism, their role in bile acid homeostasis remains elusive. METHODS: Metabolomic and transcriptomic analyses on liver-specific CBP/p300 knockout mice were performed to assess bile acid metabolism. CUT&Tag sequencing and ChIP-qPCR were used to investigate the epigenetic mechanisms underlying CBP/p300-mediated bile acid regulation. A mouse model of cholestatic liver disease was established to validate the findings from the liver-specific CBP/p300 double-knockout mice by administrating a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. RESULTS: Liver-specific CBP/p300 deletion caused intrahepatic cholestasis due to impaired bile acid efflux, along with elevated plasma bile acid levels. Transcriptomic and metabolomic analyses revealed decreased expression of bile acid synthesis and transport genes, including Abcb11 (encoding BSEP, the bile salt export pump). Mechanistically, CBP/p300 promoted Abcb11 transcription via H3K27 acetylation. In addition, CBP/p300 epigenetically regulated the transcription factor Kruppel-like transcription factor 10 (KLF10), which directly activated Abcb11 expression. Loss of CBP/p300 reduced H3K27Ac enrichment at both Klf10 and Abcb11 promoters, leading to their downregulation. Overexpression of either Klf10 or Abcb11 in CBP/p300-deficient hepatocytes partially rescued bile acid transport defects. Impaired KLF10-BSEP regulatory axis was also observed in DDC-induced model of hepatic cholestasis. CONCLUSIONS: Our findings uncover a novel CBP/p300-KLF10-BSEP regulatory axis that orchestrates bile acid transport and highlight its therapeutic potential for cholestatic liver diseases.