The hepatic compensatory response to elevated systemic sulfide promotes diabetes

Carter, Roderick N.; Gibbins, Matthew T.G.; Barrios-Llerena, Martin E.; Wilkie, Stephen E.; Freddolino, Peter L.; Libiad, Marouane; Vitvitsky, Victor; Emerson, Barry; Bihan, Thierry Le; Brice, Madara; Su, Huizhong; Denham, Scott; Homer, Natalie; Fadden, Clare Mc; Tailleux, Anne; Faresse, Nourdine; Sulpice, Thierry; Briand, François; Gillingwater, Thomas H.; Ahn, Kyo Han; Singha, Subhankar; McMaster, Claire; Hartley, Richard C.; Staels, Bart; Gray, Gillian A.; Finch, Andrew J.; Selman, Colin; Banerjee, Ruma; Morton, Nicholas M.

doi:10.1016/j.celrep.2021.109958

Cited by 13 publications

(9 citation statements)

References 111 publications

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“…Whether or not TST also contributes to antioxidant protection in the brain has not been investigated before. In Tst − /− mice, circulating thiosulfate and sulfide level were markedly elevated, while cerebral cortex displayed similar steady-state levels of sulfide and thiosulfate, as observed in the liver [43]. This indicates that the response to Tst knock-down is organ specific in this chronic but viable sulfide elevation model.…”

Section: Discussionmentioning

confidence: 52%

“…Starting from organ specificity, the free thiol antioxidant system of brain and liver revealed opposite responses in terms of GSH content. In Tst − /− mice, GSH was decreased in the cerebral cortex, while there was no difference in GSH content between the two genotypes in the liver [43]. Since NADPH/H + dependent glutathione reductase (GR) is important for the recycling of GSSG to GSH [44], its down-regulation in the brain of Tst − /− mice explains the alterations in GSSG levels observed.…”

Section: Discussionmentioning

confidence: 99%

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Thiosulfate Sulfurtransferase Deficiency Promotes Oxidative Distress and Aberrant NRF2 Function in the Brain

Luo,

Chatre,

Melhem

et al. 2023

Preprint

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Thiosulfate Sulfurtransferase Deficiency Promotes Oxidative Distress and Aberrant NRF2 Function in the Brain

Luo,

Chatre,

Melhem

et al. 2023

Preprint

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“…We also found that TST protein was elevated in HFD-fed G609G mice compared to RC fed animals, but the H 2 S-oxidising activity of this enzyme was decreased under HFD. We previously identified TST as a putative antidiabetic enzyme and demonstrated that homozygous TST knock out confers a pro-diabetogenic HFD-like phenotype in C57BL/6J mice [ 42 ]. These findings indicate an antagonistic relationship between HFD and TST activity, which might explain our observation of reduced TST activity under HFD feeding in G609G mice.…”

Section: Discussionmentioning

confidence: 99%

Hepatic hydrogen sulfide levels are reduced in mouse model of Hutchinson-Gilford progeria syndrome

Wilkie

Marcu

Carter

et al. 2023

Aging

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare human disease characterised by accelerated biological ageing. Current treatments are limited, and most patients die before 15 years of age. Hydrogen sulfide (H 2 S) is an important gaseous signalling molecule that it central to multiple cellular homeostasis mechanisms. Dysregulation of tissue H 2 S levels is thought to contribute to an ageing phenotype in many tissues across animal models. Whether H 2 S is altered in HGPS is unknown. We investigated hepatic H 2 S production capacity and transcript, protein and enzymatic activity of proteins that regulate hepatic H 2 S production and disposal in a mouse model of HGPS (G609G mice, mutated Lmna gene equivalent to a causative mutation in HGPS patients). G609G mice were maintained on either regular chow (RC) or high fat diet (HFD), as HFD has been previously shown to significantly extend lifespan of G609G mice, and compared to wild type (WT) mice maintained on RC. RC fed G609G mice had significantly reduced hepatic H 2 S production capacity relative to WT mice, with a compensatory elevation in mRNA transcripts associated with several H 2 S production enzymes, including cystathionine-γ-lyase (CSE). H 2 S levels and CSE protein were partially rescued in HFD fed G609G mice. As current treatments for patients with HGPS have failed to confer significant improvements to symptoms or longevity, the need for novel therapeutic targets is acute and the regulation of H 2 S through dietary or pharmacological means may be a promising new avenue for research.

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“…A nonfunctional mSOP due to ubiquinone deficiency in mouse kidney results in sulfide accumulation, increased oxidative stress, inhibited fatty acid oxidation and kidney failure [110]. Notably, in a mouse model depleted of TST, an adaptive hepatic response to increased systemic sulfide levels has been shown to promote diabetes [111].…”

Section: Cysteine Catabolism In the Control Of Cysteine Excess And A ...mentioning

confidence: 99%

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

et al. 2022

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In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.

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The hepatic compensatory response to elevated systemic sulfide promotes diabetes

Cited by 13 publications

References 111 publications

Thiosulfate Sulfurtransferase Deficiency Promotes Oxidative Distress and Aberrant NRF2 Function in the Brain

Thiosulfate Sulfurtransferase Deficiency Promotes Oxidative Distress and Aberrant NRF2 Function in the Brain

Hepatic hydrogen sulfide levels are reduced in mouse model of Hutchinson-Gilford progeria syndrome

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

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