2. Academic Validation
  3. Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis

Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis

  • Cell Death Dis. 2020 Sep 11;11(9):745. doi: 10.1038/s41419-020-02960-6.
Feiye Zhou  # 1,  Qianqian Liu  # 1,  Linlin Zhang  # 1,  Qin Zhu 1,  Shushu Wang 1,  Kecheng Zhu 1,  Ruyuan Deng 2,  Yun Liu 1,  Guoyue Yuan 3,  Xiao Wang 4,  Libin Zhou 5
Affiliations

Affiliations

  • 1 Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
  • 2 Department of Gastroenerology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 3 Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China.
  • 4 Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. wangxiao1976@hotmail.com.
  • 5 Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. libinzhou99@hotmail.com.
  • # Contributed equally.
PMID: 32917859 DOI: 10.1038/s41419-020-02960-6
Abstract

The histone acetyltransferases CREB-binding protein (CBP) and its paralogue p300 are transcriptional coactivators which are essential for a multitude of signaling pathways and energy homeostasis. However, the role of CBP/p300 HAT domain in regulating energy balance is still unclear. Here, C57BL/6 mice fed with either normal chow diet (NCD) or high-fat diet (HFD) were administrated with A-485, a recently reported selective inhibitor of CBP/p300 HAT activity for 1 week and the metabolic change was analyzed. The white adipose tissue (WAT) weight and adipocyte size were reduced in A-485-administrated mice, with decreased expressions of lipogenic genes and transcriptional factors. In the liver of A-485-treated mice, the lipid content and lipogenic gene expressions were lowered while the binding of forkhead box O1 (FOXO1) to glucose-6-phosphatase (G6Pc) promoter was reduced, leading to decreased expression of G6Pc. In primary mouse hepatocytes, A-485 abolished cAMP-elicited mRNA expressions of key gluconeogenic Enzymes and promoted FOXO1 protein degradation via increasing its ubiquitination. Thus, A-485 inhibits lipogenesis in WAT and liver as well as decreases hepatic glucose production via preventing FOXO1 acetylation, leading to its protein degradation through a proteasome-dependent pathway. The specific inhibition of CBP/p300 HAT will provide a novel therapeutic approach for metabolic diseases.

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