Hepatic CBP/p300 Orchestrate Amino Acid‐Driven Gluconeogenesis through Histone Crotonylation

Abstract The role of amino acid metabolism dysregulation in the development of type 2 diabetes remains elusive. Here, significant associations of human CREBBP/EP300 gene polymorphisms with circulating amino acid and glucose levels are reported. Through integrated transcriptomic, metabolomic, and CUT&Tag analyses, the molecular mechanisms underlying these correlations are investigated. Liver‐specific Crebbp / Ep300 double knockout mice display elevated plasma amino acid levels and impaired hepatic glucose production caused by the downregulation of amino acid metabolism genes, which is closely linked to altered histone crotonylation and acetylation patterns at their promoters. However, key gluconeogenic genes Pck1 and G6pc are not downregulated in knockout mice. Interestingly, the level of 2‐aminoadipic acid (2‐AAA), a biomarker of diabetes, is significantly increased due to decreased glutaryl‐CoA dehydrogenase (GCDH) expression in CBP/p300‐deficient livers. Treatment with 2‐AAA or overexpression of GCDH enhances amino acid‐driven gluconeogenesis through histone crotonylation‐mediated transcriptional activation of amino acid metabolism genes in primary mouse hepatocytes, whereas GCDH knockdown exhibits an opposite result. Furthermore, targeted hepatic knockdown of CBP/p300 markedly attenuates hepatic glucose production from amino acids in diabetic mice. In sum, these findings underscore the pivotal role of CBP/p300 in linking amino acid catabolism to gluconeogenesis through histone crotonylation in a cell‐autonomous manner.