Paul Blessy, Merta Holly, Ugrankar-Banerjee Rupali, Hensley Monica R, Tran Son, do Vale Goncalo Dias, Zacherias Lauren, Hewett Charles K, McDonald Jeffrey G, Font-Burgada Joan, Mathews Thomas P, Farber Steven A, Henne W Mike
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
Dev Cell. 2025 Apr 27. doi: 10.1016/j.devcel.2025.04.008.
Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored when compared with mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuring Drosophila, zebrafish, and mammalian hepatocytes, here we characterize the paraoxonase-like C20orf3/adipocyte plasma-membrane-associated protein (APMAP) as an ER-localized antioxidant that suppresses ER lipid oxidation to safeguard ER function. APMAP-depleted cells exhibit defective ER morphology, ER stress, and lipid peroxidation dependent on ER-oxidoreductase 1α (ERO1A), as well as sensitivity to ferroptosis and defects in ApoB-lipoprotein homeostasis. Similarly, organismal APMAP depletion in Drosophila and zebrafish perturbs ApoB-lipoprotein homeostasis. Strikingly, APMAP loss is rescued with chemical antioxidant N-acetyl-cysteine (NAC). Lipidomics identifies that APMAP loss elevates phospholipid peroxidation and boosts ceramides-signatures of lipid stress. Collectively, we propose that APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis in the ER network.
氧化应激扰乱脂质稳态并导致代谢性疾病。尽管与线粒体氧化相比被忽视，但内质网（ER）会产生活性氧，需要抗氧化质量控制。通过以果蝇、斑马鱼和哺乳动物肝细胞为特征的多生物体分析，我们在此将对氧磷酶样C20orf3/脂肪细胞质膜相关蛋白（APMAP）表征为一种内质网定位的抗氧化剂，它可抑制内质网脂质氧化以维护内质网功能。APMAP缺失的细胞表现出内质网形态缺陷、内质网应激以及依赖于内质网氧化还原酶1α（ERO1A）的脂质过氧化，以及对铁死亡的敏感性和载脂蛋白B-脂蛋白稳态缺陷。同样，果蝇和斑马鱼体内APMAP缺失会扰乱载脂蛋白B-脂蛋白稳态。引人注目的是，化学抗氧化剂N-乙酰半胱氨酸（NAC）可挽救APMAP缺失。脂质组学鉴定出APMAP缺失会增加磷脂过氧化并增强神经酰胺——脂质应激的特征。我们总体认为，APMAP是一种内质网定位的抗氧化剂，可促进内质网网络中的脂质和脂蛋白稳态。
