SIRT2 ablation inhibits glucose-stimulated insulin secretion through decreasing glycolytic flux

Zhou, Feiye; Zhang, Linlin; Zhu, Ke-Cheng; Bai, Mengyao; Zhang, Yuqing; Zhu, Qin; Wang, Shushu; Sheng, Chunxiang; Yuan, Miaomiao; Liu, Yun; Lu, Jieli; Shao, Li; Wang, Xiao; Zhou, Libin

doi:10.7150/thno.55330

Cited by 28 publications

(26 citation statements)

References 31 publications

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“…Nonetheless, hyperacetylation may affect the expression, structure, and function of ALDOA , which needs further exploration. Zhou et al study showed that SIRT2 inhibition promoted the protein degradation of ALDOA ( 87 ), which supported our hypothesis, although whether this regulation was caused by the hyperacetylation of ALDOA directly caused by SIRT2 inhibition is yet to be clarified.…”

Section: Discussionsupporting

confidence: 87%

Associative analysis of multi-omics data indicates that acetylation modification is widely involved in cigarette smoke-induced chronic obstructive pulmonary disease

Gao

Liu²,

Wang³

et al. 2023

Front. Med.

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We aimed to study the molecular mechanisms of chronic obstructive pulmonary disease (COPD) caused by cigarette smoke more comprehensively and systematically through different perspectives and aspects and to explore the role of protein acetylation modification in COPD. We established the COPD model by exposing C57BL/6J mice to cigarette smoke for 24 weeks, then analyzed the transcriptomics, proteomics, and acetylomics data of mouse lung tissue by RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), and associated these omics data through unique algorithms. This study demonstrated that the differentially expressed proteins and acetylation modification in the lung tissue of COPD mice were co-enriched in pathways such as oxidative phosphorylation (OXPHOS) and fatty acid degradation. A total of 19 genes, namely, ENO3, PFKM, ALDOA, ACTN2, FGG, MYH1, MYH3, MYH8, MYL1, MYLPF, TTN, ACTA1, ATP2A1, CKM, CORO1A, EEF1A2, AKR1B8, MB, and STAT1, were significantly and differentially expressed at all the three levels of transcription, protein, and acetylation modification simultaneously. Then, we assessed the distribution and expression in different cell subpopulations of these 19 genes in the lung tissues of patients with COPD by analyzing data from single-cell RNA sequencing (scRNA-seq). Finally, we carried out the in vivo experimental verification using mouse lung tissue through quantitative real-time PCR (qRT-PCR), Western blotting (WB), immunofluorescence (IF), and immunoprecipitation (IP). The results showed that the differential acetylation modifications of mouse lung tissue are widely involved in cigarette smoke-induced COPD. ALDOA is significantly downregulated and hyperacetylated in the lung tissues of humans and mice with COPD, which might be a potential biomarker for the diagnosis and/or treatment of COPD.

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Section: Discussionsupporting

confidence: 87%

Associative analysis of multi-omics data indicates that acetylation modification is widely involved in cigarette smoke-induced chronic obstructive pulmonary disease

Gao

Liu²,

Wang³

et al. 2023

Front. Med.

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“…Second, we provide a mechanism showing that Cyb5r3 modulates Gck stability in β cells. Gck regulatory protein (GKRP) and B cell lymphoma-2 (BCL2)–associated agonist of cell death (BAD) modulate Gck in β cells and the liver ( 21 , 38 ). In the liver, GKRP binding stabilizes Gck, which is activated upon dissociation ( 39 , 40 ).…”

Section: Discussionmentioning

confidence: 99%

Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes

Watanabe

Son

et al. 2023

Sci. Transl. Med.

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Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) down-regulation as a mechanism of secondary SU failure and successfully reverse it. Chronic exposure to SU lowered Cyb5r3 abundance and reduced islet glucose utilization in mice in vivo and in ex vivo murine islets. Cyb5r3 β cell–specific knockout mice phenocopied SU failure. Cyb5r3 engaged in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Hence, Gck activators can circumvent Cyb5r3-dependent SU failure. A Cyb5r3 activator rescued secondary SU failure in mice in vivo and restored insulin secretion in ex vivo human islets. We conclude that Cyb5r3 is a key factor in the secondary failure to SU and a potential target for its prevention, which might rehabilitate SU use in diabetes.

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“…Second, we provide a mechanism for this observation by showing that Cyb5r3 modulates Gck activity in β-cells. Gck regulatory protein (GKRP) and BAD are known to regulate Gck in β-cell and liver 22, 39 . In the liver, GKRP binding stabilizes Gck, which is activated upon dissociation 40, 41 .…”

Section: Discussionmentioning

confidence: 99%

Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea

Watanabe

Son

et al. 2022

Preprint

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Sulfonylureas (SU) are effective and affordable anti-diabetic drugs. But chronic use leads to secondary failure, limiting their utilization. The mechanism of secondary failure is unknown. Here we identify Cyb5r3 downregulation as a mechanism of SU failure and successfully reverse it. Chronic exposure to SU impairs Cyb5r3 levels and reduces islet glucose utilization with a metabolomics signature characterized by low acetyl-CoA and amino acid levels. Cyb5r3 engages in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Accordingly, activating Gck mutations in patients with hyperinsulinemia reduce Cyb5r3 binding, whereas inactivating MODY mutations increase it, providing evidence for a role of Cyb5r3 in determining flux through Gck. The Cyb5r3 activator tetrahydroindenoindole (THII) rescues secondary failure to SU in an animal model of chronic SU treatment and restores insulin secretion from ex vivo islets. We conclude that Cyb5r3 loss-of-function is a key factor in the secondary failure to SU and a potential target for its prevention, which may lead to a rehabilitation of SU use in diabetes.

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SIRT2 ablation inhibits glucose-stimulated insulin secretion through decreasing glycolytic flux

Cited by 28 publications

References 31 publications

Associative analysis of multi-omics data indicates that acetylation modification is widely involved in cigarette smoke-induced chronic obstructive pulmonary disease

Associative analysis of multi-omics data indicates that acetylation modification is widely involved in cigarette smoke-induced chronic obstructive pulmonary disease

Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes

Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea

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