The hepatic compensatory response to elevated systemic sulfide impairs medium chain fat oxidation and promotes diabetes

Carter, R. N.; Gibbins, M. T. G.; Barrios-Llerena, M. E.; Wilkie, S.; Freddolino, P.; Libiad, M.; Vitvitsky, V.; Emerson, B.; LeBihan, T.; Brice, M.; Su, H.; Denham, S.; Homer, N. Z. M.; Mc Fadden, 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.; Selman, C.; Banerjee, R.; Morton, N. M.

doi:10.1101/2020.04.27.064287

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bioRxiv · 10.1101/2020.04.27.064287

The hepatic compensatory response to elevated systemic sulfide impairs medium chain fat oxidation and promotes diabetes

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Abstract

Impaired hepatic glucose and lipid metabolism are hallmarks of type-2 diabetes. Increased sulfide production from cysteine, 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 sulfur-transferase (Tst-/- mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia and fatty liver, despite whole-body insulin-sensitisation. Unexpectedly, hepatic sulfide levels were normal in Tst-/- mice, a result of homeostatic induction of mitochondrial sulfide disposal and glutathione excretion associated with net suppression of protein persulfidation and nuclear respiratory factor-2 target proteins. Proteomic and persulfidomic profiling converged on gluconeogenesis and hepatic lipid metabolism and revealed a selective deficit in medium-chain fatty acid oxidation in Tst-/- mice. We reveal a critical role for TST in hepatic metabolism that raises implications for sulfide-donor strategies in the context of liver function and metabolic disease.

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Carter, R. N., Gibbins, M. T. G., Barrios-Llerena, M. E., Wilkie, S., Freddolino, P., Libiad, M., Vitvitsky, V., Emerson, B., LeBihan, T., Brice, M., Su, H., Denham, S., Homer, N. Z. M., Mc Fadden, 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., Selman, C., Banerjee, R., Morton, N. M.. 2020-04-29. The hepatic compensatory response to elevated systemic sulfide impairs medium chain fat oxidation and promotes diabetes. https://doi.org/10.1101/2020.04.27.064287

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