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.