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Novel zebrafish mutants reveal new roles for Apolipoprotein B during embryonic development and pathological conditions

Templehof H, Moshe N, Avraham-Davidi I, Yaniv K
bioRxiv. 2021;[preprint] doi:10.1101/2021.04.01.437990
Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs and LDLs and is essential for their assembly. Defects in ApoB synthesis and secretion result in several human diseases, including abetalipoproteinemia and familial hypobetalipoproteinemia. Conversely, high levels of APOB in plasma are associated with increased risk for coronary heart disease and atherosclerosis. The involvement of APOB in lipid metabolism and atherogenesis prompted the generation of several mutant mice. However, as APOB is required for supplying nutrients to the developing embryo, ApoB null mice are embryonic lethal, thereby precluding the study of the roles of this protein during development. Here, we established novel zebrafish mutants for two apoB genes: apoBa and apoBb.1. Double-mutant embryos display clear hallmarks of human hypolipidemia-related diseases, including intestinal defects and fatty liver, as well as profound vascular defects. We further use these models to identify the domains within ApoB responsible for its functions. By assessing the ability of different truncated forms of human APOB to rescue the mutant phenotypes, we demonstrate the benefits of this model for prospective therapeutic screens. Overall, our novel zebrafish models uncover new functions of ApoB in organ development and morphogenesis and shed new light on the mechanisms underlying hypolipidemia-related diseases.
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