The present study was performed to determine the effect of waterborne CdCl₂ exposure influencing lipid deposition and metabolism, oxidative stress and mitochondrial dysfunction, and explore the underlying molecular mechanism of cadmium (Cd)-induced disorder of hepatic lipid metabolism in fish. To this end, adult zebrafish were exposed to three waterborne CdCl₂ concentrations (0(control), 5 and 25 μg Cd/l, respectively) for 30 days. Lipid accumulation, the activities of enzymes related to lipid metabolism and oxidative stress, as well as the expression level of genes involved in lipid metabolism and mitophagy were determined in the liver of zebrafish. Waterborne CdCl₂ exposure increased hepatic triglyceride (TG) and Cd accumulation, the activities of fatty acid synthase (FAS), 6-phosphogluconate dehydrogenase (6PGD), glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME), and the mRNA level of fatty acid synthase (fas), acetyl-CoA carboxylase alpha (acaca), glucose 6-phosphate dehydrogenase (g6pd) and malic enzyme (me), but reduced the mRNA level of carnitine palmitoyl transferase 1 (cpt1), hormone-sensitive lipase alpha (hsla), and adipose triacylglyceride lipase (atgl). The activities of superoxide dismutase (SOD), glutathoinine peroxidase (GPx) and cytochrome c oxidase (COX) and the ATP level were significantly reduced after CdCl₂ exposure. CdCl₂ exposure significantly increased the mRNA level of genes (microtubule-associated protein light chain 3 alpha (lc3a), PTEN-induced putative kinase 1 (pink1), NIP3-like protein X (nix) and PARKIN (parkin)) related to mitophagy. To elucidate the mechanism, reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA) were used to verify the role of ROS and mitochondrial dysfunction in Cd-induced disorder of lipid metabolism. NAC pretreatment reversed the Cd-induced up-regulation of TG accumulation and activities of lipogenic enzymes, and the Cd-induced down-regulation of mRNA levels of lipolytic genes. Meanwhile, NAC pretreatment also blocked the mitochondrial membrane potential (MMP) collapse and decreased the ATP level, suggesting that ROS played a crucial role in regulating the Cd-induced mitochondrial dysfunction. Taken together, our findings, for the first time, highlight the importance of the oxidative stress and mitochondrial dysfunction in Cd-induced disorder of hepatic lipid metabolism, which proposed a novel mechanism for elucidating metal element exposure inducing the disorder of lipid metabolism in vertebrates.

本研究旨在确定水性CdCl ₂暴露对脂质沉积和代谢，氧化应激和线粒体功能障碍的影响，并探讨镉（Cd）诱导的鱼肝脂质代谢紊乱的潜在分子机制。为此，成年斑马鱼暴露于三种水性CdCl ₂浓度（分别为0（对照），5和25μgCd / l）30天。测定斑马鱼肝脏中的脂质蓄积，与脂质代谢和氧化应激有关的酶的活性以及与脂质代谢和线粒体吞噬有关的基因的表达水平。水性CdCl ₂暴露会增加肝甘油三酸酯（TG）和镉的积累，脂肪酸合酶（FAS），6-磷酸葡萄糖酸脱氢酶（6PGD），葡萄糖6磷酸脱氢酶（G6PD）和苹果酸酶（ME）的活性以及脂肪的mRNA水平酸合酶（fas），乙酰辅酶A羧化酶α（acaca），葡萄糖6磷酸脱氢酶（g6pd）和苹果酸酶（me），但降低了肉碱棕榈酸转移酶1（cpt1）的mRNA水平，激素敏感性脂肪酶α（hsla）和脂肪族三酰基甘油酯脂肪酶（atgl）。暴露于CdCl ₂后，超氧化物歧化酶（SOD），谷胱甘肽过氧化物酶（GPx）和细胞色素c氧化酶（COX）的活性和ATP水平显着降低。CdCl ₂暴露显着增加了基因的mRNA水平（微管相关蛋白轻链3 alpha（lc3a），PTEN诱导的假定激酶1（pink1），NIP3样蛋白X（nix）和PARKIN（parkin））与线粒体有关。为了阐明机理，使用活性氧（ROS）清除剂N-乙酰半胱氨酸（NAC）和线粒体通透性转变（MPT）抑制剂环孢菌素A（CsA）来验证ROS和线粒体功能障碍在镉诱导的脂质疾病中的作用代谢。NAC预处理逆转了Cd诱导的TG积累和脂肪酶活性的上调，以及Cd诱导的脂解基因mRNA水平的下调。同时，NAC预处理还可以阻止线粒体膜电位（MMP）崩溃并降低ATP水平，这表明ROS在调节Cd诱导的线粒体功能障碍中起着至关重要的作用。总而言之，我们的发现是第一次