Dataset Information

Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity (Proteomics)

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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Xuemei Tong

PROVIDER: PXD050130 | iProX | Mon Feb 26 00:00:00 GMT 2024

REPOSITORIES: iProX

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Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.

Tong Lingfeng L Chen Zhangbing Z Li Yangyang Y Wang Xinxia X Yang Changjie C Li Yakui Y Zhu Yemin Y Lu Ying Y Liu Qi Q Xu Nannan N Shao Sijia S Wu Lifang L Zhang Ping P Wu Guangyu G Wu Xiaoyu X Chen Xiaosong X Fang Junwei J Jia Renbing R Xu Tianle T Li Bin B Zheng Liang L Liu Junling J Tong Xuemei X

Cell metabolism 20240327 5

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 demonst ...[more]

PMID: 38547864

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Project description:Type 2 diabetes (T2D) is a growing global health crisis, largely driven by rising obesity rates. Untreated T2D leads to severe complications such as cardiovascular disease, nephropathy, retinopathy, neuropathy, and hepatic dysfunction. Current therapies primarily manage hyperglycemia but often fail to address core pathophysiological drivers like insulin resistance and obesity. This highlights an urgent need for novel therapeutics with distinct mechanisms, particularly those targeting energy metabolism and insulin sensitivity, to improve long-term T2D outcomes. Modulating mitochondrial respiration through mild uncoupling has emerged as a promising strategy to promote negative energy balance. SR4, a small-molecule mitochondrial uncoupler, represents a novel class of fatty acid-activated proton transporters. In this study, we investigated the metabolic effects of oral SR4 administration in male db/db mice model of T2D. SR4 significantly reduced body weight gain and improved body composition by selectively decreasing fat mass without affecting lean mass. Indirect calorimetry confirmed that SR4 treatment increased oxygen consumption and total energy expenditure, independent of food intake. Importantly, SR4 substantially improved glycemic control, reduced insulin resistance, and prevented dyslipidemia, hepatic steatosis, and liver injury. Mechanistically, SR4 activated hepatic AMP-activated protein kinase (AMPK), enhanced mitochondrial respiration, and mitigated oxidative stress. Liver transcriptomic profiling further demonstrated broad metabolic reprogramming, including downregulation of lipogenesis and peroxisome proliferator-activated receptor γ (PPARγ) signaling, concurrently with upregulation of genes involved in energy metabolism and antioxidant defense. Collectively, these findings demonstrate that SR4 ameliorates multiple aspects of metabolic dysfunction in an obese T2D mouse model by targeting key pathways in energy regulation and lipid metabolism. Our results provide additional mechanistic insights into the effects of mitochondrial uncouplers in the liver and support further investigation of SR4 and related fatty acid anion transporters as a novel therapeutic class for metabolic diseases.

Project description:Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.

Dataset Information

Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity (Proteomics)

Publications

Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.

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