Abstract
SummaryImpaired 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.
Highlights
The prevalence of type 2 diabetes (T2D) continues to soar in parallel with that of obesity (World Health Organization, 2016)
Dysregulation of hepatic nutrient metabolism in T2D is a promising area for therapeutic intervention because it precipitates the more severe liver pathologies that manifest along the spectrum of non-alcoholic fatty liver disease (NAFLD), Cell Reports 37, 109958, November 9, 2021 a 2021 The Authors
TstÀ/À mice exhibit increased hepatic gluconeogenesis and dyslipidemia despite mild peripheral insulin sensitization thiosulfate sulfurtransferase (TST) mRNA expression is highest in the liver
Summary
The prevalence of type 2 diabetes (T2D) continues to soar in parallel with that of obesity (World Health Organization, 2016). Because Tst deficiency is a model of chronic but viable sulfide elevation, determining the molecular mechanisms driving the aberrant metabolic profile can provide important insights into the optimal range for therapeutic sulfide exposure, in light of the current interest in developing mitochondrially targeted sulfide donors (Gero} et al, 2016; Karwi et al, 2018). To this end, we sought to define the effect of Tst deficiency on the underlying molecular pathways that affect hepatic metabolism
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