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

UNLABELLED: Oxidative 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 featuring Drosophila , 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 in Drosophila perturbs 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 SUMMARY: APMAP localizes primarily to the ER network in human cells and Drosophila fat body tissue, and is a type II integral membrane protein Loss of APMAP or Drosophila APMAP (dAPMAP) causes ER membrane expansion, elevates CHOP-associated ER stress, promotes LD accumulation, and alters ApoB-lipoprotein secretion APMAP-depleted cells and dAPMAP-depleted Drosophila fat tissue exhibit defective redox homeostasis; phenotypes associated with APMAP loss are rescued by antioxidant NAC Zebrafish-based LipoGlo reporter reveals that loss of apmap in zebrafish causes increased vascular ApoB-containing lipoproteins Lipidomic profiling indicates that APMAP loss reduces PUFA-phospholipids and elevates intracellular ceramides, which perturbs ApoB maturation.