Abstract
Apolipoprotein-B (ApoB) is the structural component of atherogenic lipoproteins, lipid-rich particles that drive atherosclerosis by accumulating in the vascular wall. As atherosclerotic cardiovascular disease is the leading cause of death worldwide, there is an urgent need to develop new strategies to prevent lipoproteins from causing vascular damage. Here we report the LipoGlo system, which uses a luciferase enzyme (NanoLuc) fused to ApoB to monitor several key determinants of lipoprotein atherogenicity including particle abundance, size, and localization. Using LipoGlo, we comprehensively characterize the lipoprotein profile of individual larval zebrafish and collect images of atherogenic lipoprotein localization in an intact organism. We report multiple extravascular lipoprotein localization patterns, as well as identify Pla2g12b as a potent regulator of lipoprotein size. ApoB-fusion proteins thus represent a sensitive and specific approach to study atherogenic lipoproteins and their genetic and small molecule modifiers.
Highlights
Indirect characterization of lipoproteins with lipid measurements, provide very limited information on properties such as the concentration and size distribution of ApoB-LPs, both of which are key determinants of atherogenic potential
Known functional elements of ApoB are well conserved in zebrafish, including both the microsomal triglyceride transfer protein (Mtp) interacting[28] and Low-density lipoproteins (LDLs)-receptor binding[29] domains (Supplementary Fig. 1a)
The APOB-48 editing site required for production of the truncated version of APOB26 appears to be completely absent in zebrafish (Supplementary Fig. 1b)
Summary
Indirect characterization of lipoproteins with lipid measurements, provide very limited information on properties such as the concentration and size distribution of ApoB-LPs, both of which are key determinants of atherogenic potential. ApoB-LP levels were measured throughout development from 1 to 6 days post fertilization (dpf) using zebrafish carrying the LipoGlo reporter in the wild-type (WT) genetic background (Fig. 2a).
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