Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations.
Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations.
复制标题
威尔逊病小鼠模型中的肝氧脂谱：对早期肝脏表现的新见解。
DOI：
10.1016/j.bbalip.2023.159446
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Medici,Valentina
中科院分区：
文献类型：
--
作者：
Mazi,TagreedA;Shibata,NoreeneM;Sarode,GauravV;Medici,Valentina
肝脏炎症通常在肝豆状核变性（WD）中发现，这是一种肝脏和脑铜蓄积的遗传性疾病。铜积累与氧化应激和活性氧生成增加有关，这可能导致膜结合多不饱和脂肪酸（PUFA）的非酶促氧化。PUFA可以通过脂氧合酶（LOX）、环氧合酶（考克斯）和细胞色素P450单加氧酶（CYP）被酶促氧化。PUFA氧化的产物统称为氧化脂质（OXL），是调节肝脏炎症的生物活性脂质。我们在两种小鼠模型中研究了WD早期阶段的肝脏OXL谱，这两种小鼠模型是来自杰克逊实验室的毒性乳鼠（tx-j）和C57 Bl/6背景下的Atp 7 b敲除小鼠（Atp 7 b −/−B6）。通过超高效液相色谱-电喷雾离子化-串联质谱进行的靶向脂质组学分析表明，在Tx-j和Atp 7 b −/−B6小鼠中，肝脏OXL谱随着血栓烷和前列腺素水平的升高而改变。氧化应激标志物9-HETE水平在tx-j小鼠中更明显地升高。然而，这两种基因型都显示与氧化应激和炎症相关的许多基因的转录水平上调。两种基因型均显示较高的胰高血糖素、血栓素沿着较高的PUFA衍生醇、二醇和酮（具有改变的环氧化物）; Alox 5的表达上调，许多CYP相关基因失调。途径分析显示花生四烯酸和亚油酸代谢失调是WD小鼠的特征。我们的研究结果表明，在早期WD的肝脏PUFA代谢的改变，并建议上调，非酶ROS依赖性和酶PUFA氧化，这可能有影响WD的肝脏表现，并代表未来治疗的潜在目标。
Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and theAtp7bknockout on a C57Bl/6 background (Atp7b−/−B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j andAtp7b−/−B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression ofAlox5was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.