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 (H2S) is an important player in the liver, impacting lipid metabolism and mitochondrial function. However, direct delivery of H2S 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.