Department of Chemistry and Biochemistry, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.
Department of Chemistry and Biochemistry, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; School of Life Science, Shanxi University, Taiyuan, China.
Life Sci. 2020 Jul 1;252:117661. doi: 10.1016/j.lfs.2020.117661. Epub 2020 Apr 16.
Hydrogen sulfide (HS) as a novel gasotransmitter can be endogenously produced in liver by cystathionine gamma-lyase (CSE). The dysfunctions of CSE/HS system have been linked to various liver diseases. Acetyl-CoA is the key intermediate from the metabolism of lipid. This study examined the roles of HS in hepatic acetyl-CoA and lipid metabolism.
Both in vitro cell model and in vivo animal model of lipid accumulation were used in this study. Western blotting and real-time PCR were used for analysis of protein and mRNA expression. Acetyl-CoA was analyzed by a coupled enzyme assay, and lipid accumulation was observed with Oil Red O staining.
Incubation of human liver carcinoma (HepG2) cells with a mixture of free fatty acids (FFAs) or high glucose reduced CSE expression and HS production, promoted intracellular accumulation of acetyl-CoA and lipid. Supply of exogenous NaHS or cysteine reduced acetyl-CoA contents and lipid accumulation, while blockage of CSE activity promoted intracellular lipid accumulation. Furthermore, HS blocked FFAs-induced transcriptions of de novo lipogenesis, inflammation, and fibrosis-related genes. In vivo, knockout of CSE gene stimulated more hepatic acetyl-CoA and lipid accumulation in mice induced by high-fat choline-deficient diet. The expressions of lipogenesis, inflammation, and fibrosis-related genes were significantly higher in liver tissues from CSE knockout mice when compared with wild-type mice.
CSE/HS system is indispensable for maintaining the homeostasis of acetyl-CoA and lipid accumulation and protecting from the development of inflammation and fibrosis in liver under excessive caloric ingestion.
作为一种新型气体递质，硫化氢（HS）可以在肝脏中由胱硫醚γ-裂解酶（CSE）内源性产生。CSE/HS 系统的功能障碍与各种肝病有关。乙酰辅酶 A 是脂质代谢的关键中间产物。本研究探讨了 HS 在肝乙酰辅酶 A 和脂质代谢中的作用。
本研究使用了体外细胞模型和体内脂肪积累动物模型。Western blot 和实时 PCR 用于分析蛋白和 mRNA 表达。通过偶联酶测定法分析乙酰辅酶 A，并用油红 O 染色观察脂质积累。
将游离脂肪酸（FFAs）或高葡萄糖混合物孵育于人肝癌（HepG2）细胞中，降低了 CSE 表达和 HS 产生，促进了细胞内乙酰辅酶 A 和脂质的积累。外源性提供 NaHS 或半胱氨酸可降低乙酰辅酶 A 含量和脂质积累，而阻断 CSE 活性则促进细胞内脂质积累。此外，HS 阻断了 FFAs 诱导的新生脂肪生成、炎症和纤维化相关基因的转录。在体内，高脂肪胆碱缺乏饮食诱导的 CSE 基因敲除小鼠肝内乙酰辅酶 A 和脂质积累增加。与野生型小鼠相比，CSE 基因敲除小鼠肝组织中脂肪生成、炎症和纤维化相关基因的表达显著升高。
在过量热量摄入下，CSE/HS 系统对于维持乙酰辅酶 A 和脂质积累的内稳态以及防止肝脏炎症和纤维化的发展是必不可少的。
