The hepatic compensatory response to elevated systemic sulfide promotes diabetes

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.