Paraoxonase-like APMAP maintains endoplasmic reticulum-associated lipid and lipoprotein homeostasis

Abstract

SummaryOxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored compared to mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuringDrosophila, zebrafish, and mammalian cells, here we characterize the paraoxonase-like APMAP as an ER-localized protein that promotes redox and lipid homeostasis and lipoprotein maturation. APMAP-depleted mammalian cells exhibit defective ER morphology, elevated ER and oxidative stress, lipid droplet accumulation, and perturbed ApoB-lipoprotein homeostasis. Critically, APMAP loss is rescued with chemical antioxidant NAC. Organismal APMAP depletion inDrosophilaperturbs fat and lipoprotein homeostasis, and zebrafish display increased vascular ApoB-containing lipoproteins, particles that are atherogenic in mammals. Lipidomics reveals altered polyunsaturated phospholipids and increased ceramides upon APMAP loss, which perturbs ApoB-lipoprotein maturation. These ApoB-associated defects are rescued by inhibiting ceramide synthesis. Collectively, we propose APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis.Key findings summaryAPMAP localizes primarily to the ER network in human cells andDrosophilafat body tissue, and is a type II integral membrane proteinLoss of APMAP orDrosophilaAPMAP (dAPMAP) causes ER membrane expansion, elevates CHOP-associated ER stress, promotes LD accumulation, and alters ApoB-lipoprotein secretionAPMAP-depleted cells and dAPMAP-depletedDrosophilafat tissue exhibit defective redox homeostasis; phenotypes associated with APMAP loss are rescued by antioxidant NACZebrafish-based LipoGlo reporter reveals that loss ofapmapin zebrafish causes increased vascular ApoB-containing lipoproteinsLipidomic profiling indicates that APMAP loss reduces PUFA-phospholipids and elevates intracellular ceramides, which perturbs ApoB maturation