Abstract

Improved understanding of lipoproteins, particles that transport lipids throughout the circulation, is vital to developing new treatments for the dyslipidemias associated with metabolic syndrome. Apolipoproteins are a key component of lipoproteins. Apolipoproteins are proteins that structure lipoproteins and regulate lipid metabolism through control of cellular lipid exchange. Constraints of cell culture and mouse models mean that there is a need for a complementary model that can replicate the complex in vivo milieu that regulates apolipoprotein and lipoprotein biology. Here, we further establish the utility of the genetically tractable and optically clear larval zebrafish as a model of apolipoprotein biology. Gene ancestry analyses were implemented to determine the closest human orthologs of the zebrafish apolipoprotein A-I (apoA-I), apoB, apoE and apoA-IV genes and therefore ensure that they have been correctly named. Their expression patterns throughout development were also analyzed, by whole-mount mRNA in situ hybridization (ISH). The ISH results emphasized the importance of apolipoproteins in transporting yolk and dietary lipids: mRNA expression of all apolipoproteins was observed in the yolk syncytial layer, and intestinal and liver expression was observed from 4–6 days post-fertilization (dpf). Furthermore, real-time PCR confirmed that transcription of three of the four zebrafish apoA-IV genes was increased 4 hours after the onset of a 1-hour high-fat feed. Therefore, we tested the hypothesis that zebrafish ApoA-IV performs a conserved role to that in rat in the regulation of food intake by transiently overexpressing ApoA-IVb.1 in transgenic larvae and quantifying ingestion of co-fed fluorescently labeled fatty acid during a high-fat meal as an indicator of food intake. Indeed, ApoA-IVb.1 overexpression decreased food intake by approximately one-third. This study comprehensively describes the expression and function of eleven zebrafish apolipoproteins and serves as a springboard for future investigations to elucidate their roles in development and disease in the larval zebrafish model.

Highlights

  • The current epidemic of metabolic syndrome has resulted in widespread morbidity and mortality due to population increases in obesity, cardiovascular disease, type II diabetes, hypertension and stroke (Grundy et al, 2005)

  • This study focuses on four major serum apolipoproteins: apolipoprotein A-I (APOA-I), apolipoprotein B (APOB), apolipoprotein E (APOE) and apolipoprotein A-IV (APOA-IV)

  • Given that apolipoproteins are essential for lipoprotein formation and dietary lipid transport, their regulation by a high-fat diet was investigated. mRNA expression of three out of the four apoA-IV paralogs was increased by a high-fat feed

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Summary

Introduction

The current epidemic of metabolic syndrome has resulted in widespread morbidity and mortality due to population increases in obesity, cardiovascular disease, type II diabetes, hypertension and stroke (Grundy et al, 2005). Characterization of lipoprotein biology is impeded without a comprehensive study of apolipoproteins, the class of over a dozen secreted, lipid-binding proteins that function as structural backbones of lipoprotein particles and regulators of cellular lipid flux through their interactions with cell surface receptors. An improved understanding of lipoproteins, which transport lipids throughout the circulation, is vital for developing new pharmaceutical treatments for lipid abnormalities associated with metabolic syndrome. Mouse and cell culture models are often used to study dyslipidemias (abnormal levels of lipids in the blood) and apolipoprotein biology. Constrains of these systems warrant development of a new model that can replicate the complex in vivo milieu that regulates lipoproteins biology

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