Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibitingde novolipogenesis and inflammationviamTOR/SREBP-1 and NF-κB signaling pathways

Abstract Background Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem with unmet clinical need. The pathogenesis of MAFLD is very complex including abnormally increased lipogenesis, chronic inflammation, mitochondrial dysfunction, and oxidative stress. A growing body of evidence suggests that hydrogen sulfide (H 2 S) is an important player in the liver, impacting lipid metabolism and mitochondrial function. However, direct delivery of H 2 S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Results Our results demonstrated that AP39 reduced fatty liver in HFD-fed mice, which was corresponded with decreased triglyceride content in the liver and plasma as well as increased GSH/GSSG ratio in the plasma. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling in the liver of HFD-fed mice. It also led to a decrease in de novo lipogenesis in the liver by downregulating mTOR/SREBP-1/SCD1 signaling pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of ATGL, a lipolysis enzyme in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of pro inflammatory markers ( Il1b, Il6, Tnf , Mcp1 ), which was due to the downregulation of mTOR/NF-κB signaling pathway. Conclusions Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders.