The hepatic compensatory response to elevated systemic sulfide promotes diabetes

Carter, R. N. et al. (2021) The hepatic compensatory response to elevated systemic sulfide promotes diabetes. Cell Reports, 37(6), 109958. (doi: 10.1016/j.celrep.2021.109958) (PMID:34758301) (PMCID:PMC8595646)

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.

• Item Type: Articles
• Additional Information: This work was funded by a Wellcome Trust New Investigator Award (100981/Z/13/Z to N.M.M.) and a Diabetes UK grant (17/0005697). R.C.H. was funded by a Medical Research Council Discovery Award (MC-PC-15076).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hartley, Professor Richard and Selman, Professor Colin and Wilkie, Mr Stephen and McMaster, Dr Claire
• Authors: Carter, R. N., Gibbins, M. T.G., Barrios-Llerena, M. E., Wilkie, S. E., Freddolino, P. L., Libiad, M., Vitvitsky, V., Emerson, B., Le Bihan, T., Brice, M., Su, H., Denham, S. G., Homer, N. Z.M., McFadden, C., Tailleux, A., Faresse, N., Sulpice, T., Briand, F., Gillingwater, T., Ahn, K. H., Singha, S., McMaster, C., Hartley, R. C., Staels, B., Gray, G. A., Finch, A. J., Selman, C., Banerjee, R., and Morton, N. M.
• College/School: College of Science and Engineering > School of Chemistry; College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cell Reports 37(6): 109958
• Publisher Policy: Reproduced under a Creative Commons License