Tetradecylthiopropionic acid induces hepatic mitochondrial dysfunction and steatosis, accompanied by increased plasma homocysteine in mice.
Tetradecylthiopropionic acid induces hepatic mitochondrial dysfunction and steatosis, accompanied by increased plasma homocysteine in mice.
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四烷基噻吩丙酸诱导肝线粒体功能障碍和脂肪变性，并伴有小鼠血浆同型半胱氨酸的增加。
DOI：
10.1186/s12944-016-0192-9
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发表时间：
2016-02-05
影响因子：
4.5
通讯作者：
Nygård O
中科院分区：
文献类型：
--
作者：
Berge RK;Bjørndal B;Strand E;Bohov P;Lindquist C;Nordrehaug JE;Svardal A;Skorve J;Nygård O
肝线粒体功能障碍在非酒精性脂肪性肝病（NAFLD）的发病机制中起重要作用。补充甲基供体已被证明可缓解NAFLD，这将该疾病与一碳代谢联系起来。因此，本研究的目的是探讨在脂肪酸类似物十四烷基硫代丙酸（TTP，一种线粒体脂肪酸氧化抑制剂）诱导肝脂肪变性过程中，同型半胱氨酸（Hcy）及胆碱氧化途径中的代谢物的调节情况。
小鼠分别喂食对照饮食，或含0.3%、0.6%或0.9%（w/w）TTP的饮食，持续14天。收集血液和肝脏样本，分析肝脏中的酶活性和基因表达，肝脏和血浆中的脂质及脂肪酸组成，血浆中的一碳代谢物、B族维生素状态、肉碱和酰基肉碱。
肝脏线粒体脂肪酸氧化降低了40%，并且脂肪变性呈剂量依赖性诱导；与对照组相比，用0.3% TTP处理的动物总脂质增加了1.6倍，用0.6% TTP处理的增加了2倍，用0.9% TTP处理的增加了2.1倍。肝脏中较高的脂肪酸浓度与碳链长度缩短有关。此外，在最高剂量的TTP作用下，受抑制的脂肪酸氧化导致血浆肉碱降低30倍，乙酰肉碱降低9.3倍，同时棕榈酰肉碱蓄积。与对照饮食相比，给予TTP与血浆总Hcy升高（对照组：7.2±0.3 μmol/L，0.9% TTP：30.5±5.9 μmol/L）以及一碳代谢物甜菜碱、二甲基甘氨酸、肌氨酸和甘氨酸增加1.4 - 1.6倍有关，同时伴有Hcy和胆碱代谢的不同B族维生素依赖途径的基因表达变化。总Hcy与肝脏甘油三酯之间呈正相关。
TTP诱导的线粒体脂肪酸氧化抑制与肝脏氧化应激或炎症增加无关。我们的数据表明在小鼠中线粒体功能障碍与一碳代谢中的甲基化过程之间存在联系。
Hepatic mitochondrial dysfunction plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methyl donor supplementation has been shown to alleviate NAFLD, connecting the condition to the one-carbon metabolism. Thus, the objective was to investigate regulation of homocysteine (Hcy) and metabolites along the choline oxidation pathway during induction of hepatic steatosis by the fatty acid analogue tetradecylthiopropionic acid (TTP), an inhibitor of mitochondrial fatty acid oxidation. Mice were fed a control diet, or diets containing 0.3 %, 0.6 %, or 0.9 % (w/w) TTP for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, lipid and fatty acid composition in liver and plasma, one-carbon metabolites, B-vitamin status, carnitine and acylcarnitines were analyzed in plasma. Liver mitochondrial fatty acid oxidation decreased by 40 % and steatosis was induced in a dose dependent manner; total lipids increased 1.6-fold in animals treated with 0.3 % TTP, 2-fold with 0.6 % TTP and 2.1 fold with 0.9 % TTP compared to control. The higher hepatic concentration of fatty acids was associated with shortening of carbon-length. Furthermore, the inhibited fatty acid oxidation led to a 30-fold decrease in plasma carnitine and 9.3-fold decrease in acetylcarnitine at the highest dose of TTP, whereas an accumulation of palmitoylcarnitine resulted. Compared to the control diet, TTP administration was associated with elevated plasma total Hcy (control: 7.2 ± 0.3 umol/L, 0.9 % TTP: 30.5 ± 5.9 umol/L) and 1.4-1.6 fold increase in the one-carbon metabolites betaine, dimethylglycine, sarcosine and glycine, accompanied by changes in gene expression of the different B-vitamin dependent pathways of Hcy and choline metabolism. A positive correlation between total Hcy and hepatic triacylglycerol resulted. The TTP-induced inhibition of mitochondrial fatty acid oxidation was not associated with increased hepatic oxidative stress or inflammation. Our data suggest a link between mitochondrial dysfunction and the methylation processes within the one-carbon metabolism in mice.