Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity

Lingfeng Tong; Zhangbing Chen; Yangyang Li; Xinxia Wang; Changjie Yang; Yakui Li; Yemin Zhu; Ying Lu; Qi Liu; Nannan Xu; Sijia Shao; Lifang Wu; Ping Zhang; Guangyu Wu; Xiaoyu Wu; Xiaosong Chen; Junwei Fang; Renbing Jia; Tianle Xu; Bin Li; Liang Zheng; Junling Liu; Xuemei Tong

doi:10.1016/j.cmet.2024.03.003

Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity

Cell Metab. 2024 Mar 23:S1550-4131(24)00082-2. doi: 10.1016/j.cmet.2024.03.003. Online ahead of print.

Authors

Lingfeng Tong¹, Zhangbing Chen¹, Yangyang Li², Xinxia Wang¹, Changjie Yang³, Yakui Li¹, Yemin Zhu¹, Ying Lu⁴, Qi Liu⁵, Nannan Xu¹, Sijia Shao¹, Lifang Wu¹, Ping Zhang¹, Guangyu Wu⁶, Xiaoyu Wu⁷, Xiaosong Chen³, Junwei Fang⁸, Renbing Jia⁹, Tianle Xu¹⁰, Bin Li¹¹, Liang Zheng⁷, Junling Liu¹², Xuemei Tong¹³

Affiliations

¹ Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Unit of Immune and Metabolic Regulation, School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
³ Department of Liver Surgery, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
⁴ Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
⁵ Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
⁶ Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
⁷ Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
⁸ Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200032, China.
⁹ Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
¹⁰ Center for Brain Science of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
¹¹ Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
¹² Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Synvida Biotechnology Co., Ltd, Shanghai, China. Electronic address: liujl@shsmu.edu.cn.
¹³ Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xuemeitong@shsmu.edu.cn.

PMID: 38547864
DOI: 10.1016/j.cmet.2024.03.003

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.

Keywords: GalNAc-siRNA conjugates; MAFLD; inosine; metabolic dysfunction-associated fatty liver disease; mitochondrial function; transketolase.