Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations

IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. Molecular and cell biology of lipids Pub Date : 2023-12-09 DOI:10.1016/j.bbalip.2023.159446
Tagreed A. Mazi , Noreene M. Shibata , Gaurav V. Sarode , Valentina Medici
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Abstract

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 the Atp7b knockout 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 and Atp7b−/−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 of Alox5 was 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.

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威尔逊氏病小鼠模型的肝脏氧脂蛋白谱:早期肝脏表现的新见解
肝脏炎症常见于威尔逊病(WD),这是一种肝脏和大脑铜积聚的遗传疾病。铜蓄积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)的非酶氧化。多不饱和脂肪酸可通过脂氧合酶 (LOX)、环氧化酶 (COX) 和细胞色素 P450 单氧化酶 (CYP) 进行酶促氧化。PUFA 氧化产物统称为氧脂素(OXL),是一种生物活性脂质,可调节肝脏炎症。我们研究了两种小鼠模型(杰克逊实验室的毒奶小鼠(tx-j)和 C57Bl/6 背景的 Atp7b 基因敲除小鼠(Atp7b-/-B6))在 WD 早期阶段的肝脏 OXL 特征。通过超高效液相色谱-电喷雾离子化-串联质谱法进行的靶向脂质体分析表明,tx-j 和 Atp7b-/-B6 小鼠的肝脏 OXL 图谱都发生了改变,血栓素和前列腺素的水平较高。氧化应激标记物 9-HETE 的水平在 tx-j 小鼠中增加得更明显。然而,两种基因型都显示出许多与氧化应激和炎症相关的基因转录水平上调。两种基因型都表现出较高的 PUFA 衍生醇、二元醇和酮以及环氧化物的改变;Alox5 的表达上调,许多 CYP 相关基因失调。通路分析表明,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,WD 早期肝脏中的 PUFA 代谢发生了改变,并表明非酶依赖性 ROS 和酶依赖性 PUFA 氧化都发生了上调,这可能对 WD 的肝脏表现产生影响,并成为未来治疗的潜在靶点。
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来源期刊
CiteScore
11.00
自引率
2.10%
发文量
109
审稿时长
53 days
期刊介绍: BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.
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