The hepatic compensatory response to elevated systemic sulfide promotes diabetes

Area of Science:

• Biochemistry
• Metabolic Disease
• Molecular Biology

Background:

• Type 2 diabetes is characterized by impaired hepatic glucose and lipid metabolism.
• Sulfide metabolism plays a role in regulating hepatic functions.
• The sulfide oxidation pathway (SOP) is essential for managing sulfide levels.

Purpose of the Study:

• To investigate the role of thiosulfate sulfurtransferase (TST), a key enzyme in the SOP, in hepatic metabolism.
• To understand the consequences of TST deficiency on glucose and lipid metabolism in a mouse model.

Main Methods:

• Utilized Tst knockout mice (Tst-/-) to study the effects of TST deficiency.
• Analyzed hepatic glucose production, lipid profiles, and fatty liver.
• Performed proteomic and persulfidomic analyses to assess protein modifications and identify affected metabolic pathways.

Main Results:

• Tst-/- mice exhibited hypertriglyceridemia, increased gluconeogenesis, and fatty liver.
• Despite high circulating sulfide, hepatic sulfide levels were normal due to enhanced sulfide disposal.
• Identified a selective deficit in medium-chain fatty acid oxidation in Tst-/- mice.
• Observed suppressed protein persulfidation and reduced levels of nuclear respiratory factor 2 target proteins.

Conclusions:

• Thiosulfate sulfurtransferase (TST) plays a critical role in maintaining hepatic glucose and lipid homeostasis.
• TST deficiency leads to metabolic dysfunction through altered sulfide handling and impaired fatty acid oxidation.
• Findings have implications for therapeutic strategies using sulfide donors in metabolic diseases like type 2 diabetes.