Abstract
“Lipotoxicity” induced by free fatty acids (FAs) plays a central role in the pathogenesis of many metabolic diseases, with few treatment options available today. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, has been reported to have a variety of pharmacological properties, but its effect on FAs metabolism remains unclear. The purpose of this study was to investigate the effect and mechanisms of anethole dithiolethione (ADT, a sustained-release H2S donor) on hepatic FAs metabolism. ADT was administered daily for 4 weeks in male Syrian golden hamsters fed a high fat diet (HFD), and FAs profiles of liver tissues were analyzed using GC-MS. The results showed that in HFD-fed hamsters, ADT treatment significantly reduced the accumulation of toxic saturated and monounsaturated fatty acids (C16:0, C18:0, C16:1, and C18:1n9), while increased the content of n-6 and n-3 series polyunsaturated fatty acids (C20:3n6, C20:4n6, and C22:6n3). Mechanistically, ADT obviously inhibited the overexpression of acetyl-CoA carboxylase1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase1 (SCD1), and up-regulated the levels of fatty acid transport proteins (FATPs), liver fatty acid binding protein (L-FABP), carnitine palmitoyltransferase 1α (CPT1α), fatty acid desaturase (FADS)1 and FADS2. Notably, ADT administration significantly promoted Mitofusin1-mediated mitochondrial fusion and fatty acid β-oxidation. These findings suggest that ADT plays a beneficial role by regulating the synthesis, desaturation, β-oxidation, uptake, binding/isolation, and transport of FAs. In conclusion, ADT is effective in improving FAs metabolic disorders and liver injuries caused by HFD, which renders ADT a candidate drug for lipotoxicity-induced diseases.
Highlights
Fatty acids (FAs) are indispensable sources of energy in cells, and important bioactive mediators involved in many homeostasis processes, including metabolism and regulating inflammatory immune responses (Masoodi et al, 2015)
Quantitative changes of 13 free fatty acids (FFAs) detected by GC-MS in hamster liver in different experimental groups are shown in Table 3 (n = 9)
These data indicated that total saturated fatty acids (SFAs) and monounsaturated fatty acid (MUFA) increased significantly in the high fat diet (HFD) group compared to the control group
Summary
Fatty acids (FAs) are indispensable sources of energy in cells, and important bioactive mediators involved in many homeostasis processes, including metabolism and regulating inflammatory immune responses (Masoodi et al, 2015). Accumulating data suggest that abnormal FAs metabolism and its induced lipotoxicity are closely related to the risk of developing non-alcoholic fatty liver disease (NAFLD), diabetes, atherosclerosis, heart failure, and even multiple cancers (Afonso et al, 2016; Blucher and Stadler, 2017; Cansancao et al, 2018; Jiang et al, 2019; Zhou et al, 2019). The liver is the main metabolic organ of FAs, and the imbalance in its synthesis, uptake and disposal (mainly including mitochondrial oxidation and endoplasmic reticulum reesterification) will induce lipotoxicity, further leading to the body dysfunction. Mitochondrial b-oxidation, the most important metabolic pathway of FAs, is mainly regulated by rate-limiting enzymes such as carnitine palmitoyl-transferase 1a (CPT1a), which serves as a gatekeeper for FAs to enter mitochondria. There are no published data on the relationship between liver FAs metabolism and Mitofusin expression during nutrient oversupply
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
