Zhao Chengcheng, Yu Nannan, Li Wenqun, Cai Hualin, Liu Mouze, Hu Yanjie, Liu Yiping, Tang Mimi
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacy, Central South University, Changsha, China.
Front Pharmacol. 2020 Sep 23;11:549377. doi: 10.3389/fphar.2020.549377. eCollection 2020.
"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 (HS), 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 HS 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.
游离脂肪酸（FAs）诱导的“脂毒性”在许多代谢性疾病的发病机制中起核心作用，目前几乎没有有效的治疗方法。硫化氢（HS）作为一种新型气体信号分子，已被报道具有多种药理特性，但其对脂肪酸代谢的影响仍不清楚。本研究旨在探讨茴香脑二硫醇硫酮（ADT，一种缓释HS供体）对肝脏脂肪酸代谢的影响及其机制。对雄性叙利亚金仓鼠喂食高脂饮食（HFD），并每天给予ADT，持续4周，然后用气相色谱 - 质谱联用仪（GC-MS）分析肝组织中的脂肪酸谱。结果表明，在喂食HFD的仓鼠中，ADT治疗显著降低了有毒饱和脂肪酸和单不饱和脂肪酸（C16:0、C18:0 C16:1和C18:1n9）的积累，同时增加了n-6和n-3系列多不饱和脂肪酸（C20:3n6、C20:4n6和C22:6n3）的含量。机制上，ADT明显抑制乙酰辅酶A羧化酶1（ACC1）、脂肪酸合酶（FAS）和硬脂酰辅酶A去饱和酶1（SCD1）的过表达，并上调脂肪酸转运蛋白（FATP）、肝脏脂肪酸结合蛋白（L-FABP）、肉碱棕榈酰转移酶1α（CPT1α）、脂肪酸去饱和酶（FADS）1和FADS2的水平。值得注意的是，给予ADT显著促进了线粒体融合蛋白1介导的线粒体融合和脂肪酸β-氧化。这些发现表明，ADT通过调节脂肪酸的合成、去饱和、β-氧化、摄取、结合/隔离和转运发挥有益作用。总之，ADT可有效改善HFD引起的脂肪酸代谢紊乱和肝损伤，这使ADT成为脂毒性诱导疾病的候选药物。
