Cth/Mpst double ablation results in early onset fatty liver disease in lean mice.

Metabolic dysfunction-associated fatty liver disease (MAFLD), a condition that stems from hepatic lipid accumulation in the absence of liver damage and overt inflammation, has become the most common hepatic disorder worldwide. Hydrogen sulfide (H(2)S), a gasotrasmitter, endogenously generated mainly by cystathionine-γ lyase (CTH), cystathionine-β synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) enzymes, exhibits protective effect in steatosis. Herein, we have demonstrated that CTH and MPST play a central role in MAFLD pathogenesis. Young Cth/Mpst knockout (Cth/Mpst(-/-)) mice, fed a normal diet, had increased liver mass caused by enhanced hepatic lipid accumulation. Decreased insulin and glucose sensitivity was observed in CTH/MPST-deficient mice. At the cellular level, CTH/MPST inhibition resulted in increased lipid deposition and glucose uptake in hepatocytes. Transcriptome analysis revealed significant upregulation of cholesterol biosynthesis and SREBP-related genes in the liver of Cth/Mpst(-/-) mice. Transcription factor enrichment analysis of differentially expressed genes between two genotypes, revealed a major impact of LXR, RXR and PPARA in the observed phenotype. Sulfide donor (SG1002) treatment attenuated the fatty liver disease of CTH/MPST-deficient mice. Our findings underline the importance of endogenously produced H(2)S in the pathogenesis of MAFLD and introduce the Cth/Mpst(-/-) mouse as a new animal model of early onset hepatic steatosis.