Abstract
Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs, and LDLs and is essential for their production. Defects in ApoB synthesis and secretion result in several human diseases, including abetalipoproteinemia and familial hypobetalipoproteinemia (FHBL1). In addition, ApoB-related dyslipidemia is linked to nonalcoholic fatty liver disease (NAFLD), a silent pandemic affecting billions globally. Due to the crucial role of APOB in supplying nutrients to the developing embryo, ApoB deletion in mammals is embryonic lethal. Thus, a clear understanding of the roles of this protein during development is lacking. Here, we established zebrafish mutants for 2 apoB genes: apoBa and apoBb.1. Double-mutant embryos displayed hepatic steatosis, a common hallmark of FHBL1 and NAFLD, as well as abnormal liver laterality, decreased numbers of goblet cells in the gut, and impaired angiogenesis. We further used these mutants 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, these zebrafish models uncover what are likely previously undescribed functions of ApoB in organ development and morphogenesis and shed light on the mechanisms underlying hypolipidemia-related diseases.
Highlights
Apolipoprotein B (ApoB) is the primary structural component of atherogenic lipoproteins, such as chylomicrons, VLDLs, and LDLs, and is essential for their assembly [1]
Three apoB genes are detected in the zebrafish genome: apoBa, apoBb.1, and apoB.2 [14, 19]
At 5 dpf, apoBa expression became restricted to the liver (Figure 1C, arrowhead), and apoB.1 was detected mostly in the yolk syncytial layer (YSL) and the intestine (Figure 1D)
Summary
Apolipoprotein B (ApoB) is the primary structural component of atherogenic lipoproteins, such as chylomicrons, VLDLs, and LDLs, and is essential for their assembly [1]. Besides the important role of APOB in lipid metabolism, a large body of data, accumulated during the past years, has revealed new roles for lipoproteins as signaling mediators in various cell types, operating at different levels and through various classic and nonclassic mechanisms [2]. Defects in ApoB synthesis and secretion, resulting from mutations in the ApoB, microsomal triglyceride transfer protein (MTP), and proprotein convertase subtilisin/kexin type 9 genes, lead to abetalipoproteinemia (ABL) and familial hypobetalipoproteinemia ABL and homozygous FHBL display similar clinical symptoms, including steatorrhea, neurological dysfunction, ophthalmologic abnormalities, and fatty liver. Since both disorders carry a reduced risk of cardiovascular diseases (CVDs), research into the underlying molecular mechanisms could uncover attractive targets for lipid-lowering therapies in patients with hypercholesterolemia
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