Deficiency of cystathionine gamma-lyase and hepatic cholesterol accumulation during mouse fatty liver development
Deficiency of cystathionine gamma-lyase and hepatic cholesterol accumulation during mouse fatty liver development
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DOI：
10.1007/s11434-014-0722-7
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发表时间：
2015-02-01
期刊：
影响因子：
18.9
通讯作者：
Wang, Rui
中科院分区：
文献类型：
--
作者：
Mani, Sarathi;Li, Hongzhu;Wang, Rui
肝脏脂质代谢异常是脂肪肝发展的关键组成部分，通过脂肪变性在肝脏中沉积过量脂肪。胱硫醚γ-裂解酶（CSE）是催化肝脏中硫化氢（H2S）产生的酶之一。本研究的目的是探讨CSE/H2S在肝脏调节胆固醇和脂肪酸代谢中的作用。分析用高脂饮食（HFD）喂养的野生型（WT）和CSE敲除（CSE-KO）小鼠的肝脏形态学和生化变化。喂食CSE-KO小鼠而非WT小鼠的HFD显著增加血浆和肝脏中的胆固醇水平以及肝脏和胆囊的大小。CSE-KO小鼠肝功能损害后出现典型的脂肪肝组织学和生化改变。HFD喂养的CSE-KO小鼠的血浆和肝脏甘油三酯水平显著低于HFD喂养的WT小鼠。此外，在对照饮食或HFD喂养的CSE-KO小鼠中，肝脏中核受体转录因子，特别是LXR α的表达均降低。CYP 7A 1（一种LXR α靶向基因）的表达降低，阻止胆固醇进入胆汁，随后导致胆固醇在肝脏和胆囊中蓄积。由于CSE/H2S通路的缺陷导致对HFD诱导的脂肪肝的高度易感性，因此靶向肝脏中的CSE/H2S通路可能是对抗脂肪肝损伤发展的新策略。
Abnormal hepatic lipid metabolism is a key component of fatty liver development with excess fat deposition in the liver through steatosis. Cystathionine gamma-lyase (CSE) is one of the enzymes that catalyze hydrogen sulfide (H2S) production in the liver. The aim of the present study was to investigate the role of CSE/H2S in hepatic regulation of cholesterol and fatty acid metabolism. Wild-type (WT) and CSE knockout (CSE-KO) mice fed with high-fat diet (HFD) were analyzed for liver morphological and biochemical changes. HFD feeding of CSE-KO mice, not WT mice, markedly increased cholesterol levels in plasma and livers, and the sizes of the liver and gall bladder. Typical histological and biochemical changes of fatty liver disease were found in CSE-KO mice with damaged liver functions. The levels of plasma and liver triglyceride were significantly lower in HFD-fed CSE-KO mice than in HFD-fed WT mice. Moreover, the expression of nuclear receptors transcriptional factors, especially LXR alpha, in the liver was decreased in both control diet- or HFD-fed CSE-KO mice. Decreased expression of CYP7A1, an LXR alpha targeted gene, halted catabolism of cholesterol into bile and subsequently led to cholesterol accumulation in the liver and gall bladder. Since deficiency in CSE/H2S pathway results in high susceptibility to HFD-induced fatty liver, targeting at CSE/H2S pathway in the liver may represent a novel strategy against the development of fatty liver damage.