دورية أكاديمية
Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.
| العنوان: | Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity. |
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| المؤلفون: | Tong L; 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., Chen Z; 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., Li Y; Unit of Immune and Metabolic Regulation, School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China., Wang X; 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., Yang C; Department of Liver Surgery, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China., Li Y; 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., Zhu Y; 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., Lu Y; 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., Liu Q; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., Xu N; 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., Shao S; 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., Wu L; 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., Zhang P; 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., Wu G; Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China., Wu X; 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., Chen X; Department of Liver Surgery, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China., Fang J; 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., Jia R; Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China., Xu T; 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., Li B; Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China., Zheng L; 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., Liu J; 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., Tong X; 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. |
| المصدر: | Cell metabolism [Cell Metab] 2024 May 07; Vol. 36 (5), pp. 1013-1029.e5. Date of Electronic Publication: 2024 Mar 27. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101233170 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-7420 (Electronic) Linking ISSN: 15504131 NLM ISO Abbreviation: Cell Metab Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, Mass. : Cell Press, c2005- |
| مواضيع طبية MeSH: | Inosine*/metabolism , Mitochondria*/metabolism , Mitochondria*/drug effects , Transketolase*/metabolism, Animals ; Female ; Humans ; Male ; Mice ; Hyperinsulinism/metabolism ; Liver/metabolism ; Mice, Inbred C57BL ; Mice, Knockout |
| مستخلص: | 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. Competing Interests: Declaration of interests B.L. is a co-founder of Biotheus Inc and chairman of its scientific advisory board. J.L. is a co-founder of Shanghai Synvida Biotechnology Co. Ltd. X.T. has a patent related to transketolase therapy for metabolic disorders. (Copyright © 2024 Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: GalNAc-siRNA conjugates; MAFLD; inosine; metabolic dysfunction-associated fatty liver disease; mitochondrial function; transketolase |
| المشرفين على المادة: | 5A614L51CT (Inosine) EC 2.2.1.1 (Transketolase) |
| تواريخ الأحداث: | Date Created: 20240328 Date Completed: 20240508 Latest Revision: 20240529 |
| رمز التحديث: | 20240529 |
| DOI: | 10.1016/j.cmet.2024.03.003 |
| PMID: | 38547864 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1932-7420 |
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| DOI: | 10.1016/j.cmet.2024.03.003 |