Transketolase promotes MAFLD by

limiting inosine-induced
mitochondrial activity
Lingfeng Tong 1, Zhangbing Chen 1, Yangyang Li 2, Xinxia Wang 1, Changjie Yang 3, Yakui
Li 1, Yemin Zhu 1, Ying Lu 4, Qi Liu 5, Nannan Xu 1, Sijia Shao 1, Lifang Wu 1, Ping
Zhang 1, Guangyu Wu 6, Xiaoyu Wu 7, Xiaosong Chen 3, Junwei Fang 8, Renbing Jia 9, Tianle
Xu 10, Bin Li 11, Liang Zheng 7, Junling Liu 12, Xuemei Tong 13
Affiliations expand

 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.

Copyright © 2024 Elsevier Inc. All rights reserved.

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Conflict of interest statement

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.