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 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. [Display omitted] •TST deficiency elevates sulfide, invoking exaggerated hepatic sulfide disposal•Exaggerated sulfide disposal triggers global hepatic protein underpersulfidation•Skewed persulfidation is associated with higher gluconeogenesis and impaired fat oxidation•Diabetogenic hepatic metabolism dominates over apparent peripheral insulin sensitization Carter et al. show that mice lacking the mitochondrial sulfide oxidation pathway enzyme TST have high systemic sulfide levels that invoke an alternative hepatic sulfide disposal strategy. Consequently, hepatic metabolism is dominantly skewed toward a diabetogenic profile despite peripheral insulin sensitization. This has implications for sulfide donor therapeutic agents.