2. Academic Validation
  3. BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA

BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA

  • Cell Death Dis. 2024 Oct 10;15(10):736. doi: 10.1038/s41419-024-07071-0.
Feiye Zhou # 1 2 3,  Chunxiang Sheng # 1 2,  Xiaoqin Ma # 1 2,  Tianjiao Li 1 2,  Xing Ming 1 2,  Shushu Wang 1 2,  Jialin Tan 1 2,  Yulin Yang 1 2,  Haipeng Sun 4,  Jieli Lu 1 2,  Jianmin Liu 1 2,  Ruyuan Deng 5,  Xiao Wang 6 7,  Libin Zhou 8 9
Affiliations

Affiliations

  • 1 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 2 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 3 Department of Endocrine and Metabolic Diseases, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 4 NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Center for Cardiovascular Diseases, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
  • 5 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 200032, China; Shanghai Institute of Liver Disease, Shanghai, 200032, China. deng.ruyuan@zs-hospital.sh.cn.
  • 6 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. wangxiao1976@hotmail.com.
  • 7 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. wangxiao1976@hotmail.com.
  • 8 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. libinzhou99@hotmail.com.
  • 9 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. libinzhou99@hotmail.com.
  • # Contributed equally.
PMID: 39389936 DOI: 10.1038/s41419-024-07071-0
Abstract

Elevated circulating branched-chain Amino acids (BCAAs) are tightly linked to an increased risk in the development of type 2 diabetes mellitus. The rate limiting Enzyme of BCAA catabolism branched-chain α-ketoacid dehydrogenase (BCKDH) is phosphorylated at E1α subunit (BCKDHA) by its kinase (BCKDK) and inactivated. Here, the liver-specific BCKDK or BCKDHA knockout mice displayed normal glucose tolerance and Insulin sensitivity. However, knockout of BCKDK in the liver inhibited hepatic glucose production as well as the expression of key gluconeogenic Enzymes. No abnormal gluconeogenesis was found in mice lacking hepatic BCKDHA. Consistent with the vivo results, BT2-mediated inhibition or genetic knockdown of BCKDK decreased hepatic glucose production and gluconeogenic gene expressions in primary mouse hepatocytes while BCKDK overexpression exhibited an opposite effect. Whereas, gluconeogenic gene expressions were not altered in BCKDHA-silenced hepatocytes. Mechanistically, BT2 treatment attenuated the interaction of cAMP response element binding protein (CREB) with CREB-binding protein and promoted FOXO1 protein degradation by increasing its ubiquitination. Our findings suggest that BCKDK regulates hepatic gluconeogenesis through CREB and FOXO1 signalings, independent of BCKDHA-mediated BCAA catabolism.

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