1. The hepatic compensatory response to elevated systemic sulfide promotes diabetes.
- Author
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Carter RN, Gibbins MTG, Barrios-Llerena ME, Wilkie SE, Freddolino PL, Libiad M, Vitvitsky V, Emerson B, Le Bihan T, Brice M, Su H, Denham SG, Homer NZM, Mc Fadden C, Tailleux A, Faresse N, Sulpice T, Briand F, Gillingwater T, Ahn KH, Singha S, McMaster C, Hartley RC, Staels B, Gray GA, Finch AJ, Selman C, Banerjee R, and Morton NM
- Subjects
- Animals, Diabetes Mellitus etiology, Diabetes Mellitus metabolism, Dyslipidemias etiology, Dyslipidemias metabolism, Glucose metabolism, Lipid Metabolism, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2 metabolism, Proteome metabolism, Diabetes Mellitus pathology, Dyslipidemias pathology, Gluconeogenesis, Liver pathology, Sulfides metabolism, Thiosulfate Sulfurtransferase physiology
- Abstract
Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver- enriched mitochondrial SOP enzyme thiosulfate sulfurtransferase (Tst
-/- mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia, and fatty liver. Unexpectedly, hepatic sulfide levels are normal in Tst-/- mice because of exaggerated induction of sulfide disposal, with associated suppression of global protein persulfidation and nuclear respiratory factor 2 target protein levels. Hepatic proteomic and persulfidomic profiles converge on gluconeogenesis and lipid metabolism, revealing a selective deficit in medium-chain fatty acid oxidation in Tst-/- mice. We reveal a critical role of TST in hepatic metabolism that has implications for sulfide donor strategies in the context of metabolic disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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