Hepatic CREB Binding Protein/E1A Binding Protein p300 Maintain Bile Acid Homeostasis Through Histone Acetylation-Mediated Kruppel-Like Transcription Factor 10-Bile Salt Export Pump Axis

Background & aims: Disruption of bile acid metabolism contributes to various liver diseases. Although CREB binding protein/E1A binding protein p300 are known regulators of hepatic metabolism, their role in bile acid homeostasis remains elusive.

Methods: Metabolomic and transcriptomic analyses on liver-specific CREB binding protein/E1A binding protein p300 knockout mice were performed to assess bile acid metabolism. Cleavage Under Targets & Tagmentation Sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to investigate the epigenetic mechanisms underlying CREB binding protein/E1A binding protein p300-mediated bile acid regulation. A mouse model of cholestatic liver disease was established to validate the findings from the liver-specific CREB binding protein/E1A binding protein p300 double-knockout mice by administrating a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet.

Results: Liver-specific CREB binding protein/E1A binding protein 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, CREB binding protein/E1A binding protein p300 epigenetically regulated the transcription factor Kruppel-like transcription factor 10, which directly activated Abcb11 expression. Loss of CREB binding protein/E1A binding protein p300 reduced H3K27Ac enrichment at both Klf10 and Abcb11 promoters, leading to their downregulation. Overexpression of either Klf10 or Abcb11 in CREB binding protein/E1A binding protein p300-deficient hepatocytes partially rescued bile acid transport defects. Impaired Kruppel-like transcription factor 10-bile salt export pump regulatory axis was also observed in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced model of hepatic cholestasis.

Conclusions: Our findings uncover a novel CREB binding protein/E1A binding protein p300-Kruppel-like transcription factor 10-bile salt export pump regulatory axis that orchestrates bile acid transport and highlight its therapeutic potential for cholestatic liver diseases.