Aberrant lipid metabolism contributes to the etiology of multiple human diseases including cardiovascular disease (CVD), obesity, and insulin resistance (IR). A major impediment to improving our understanding of lipid metabolism and its related disorders is that so few metabolic studies have been carried out in live organisms. As a result, the dynamic regulatory signals that coordinate absorption and transport of fatty acids (FA), and morphogenesis and fat storage in adipose tissues, remain unclear. To address this gap, the assembled research team has pioneered methods to image lipid uptake, transport and storage, within complex organs composed of many cell types in live zebrafish. The Farber lab has established tools to visualize the cellular dynamics of dietary FA in zebrafish larvae, while the Rawls lab has developed complementary methods for using vital fluorescent lipophilic dyes to visualize zebrafish adipose tissues. These state-of-the-art in vivo optical reporters provide a comprehensive view of organ physiology not revealed in previous studies of just organ development. We propose to use these methods to screen mutant lines generated by the Zebrafish Mutation Resource under the direction of Dr. Derek Stemple. We will first conduct a primary screen to identify mutants defective in digestive organ lipid uptake, metabolism, transport and storage by feeding fluorescent lipids and lipophilic dyes and assaying their patterns of accumulation in live larvae. We will then conduct secondary screens to comprehensively characterize the phenotypes of identified lipid metabolism and adipose tissue mutants. The overall objective of the proposed research is to identify important genetic modifiers of lipid uptake, transport, and storage in the zebrafish. The rationale is that, once the genetic pathways regulating zebrafish lipid metabolism are known, this information could be translated to humans to initiate new therapeutic approaches to reduce risk of CVD, obesity, IR, and associated disorders by controlling distinct lipid metabolic processes in selected tissues.

Public Health Relevance

Our long-term goal is to understand the mechanisms by which digestive organs absorb and process dietary lipids (fat). In the US and Canada, approximately one in eleven adults has diabetes and one in three children is obese, and the associated diseases have the highest morbidity rate and contribute the greatest to public health care spending. We have developed a system that can ultimately identify pharmaceutical drugs to treat obesity and metabolic disorders by using zebrafish to perform experiments not possible in mammals.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Karp, Robert W
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Carnegie Institution of Washington, D.C.
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Minchin, James E N; Scahill, Catherine M; Staudt, Nicole et al. (2018) Deep phenotyping in zebrafish reveals genetic and diet-induced adiposity changes that may inform disease risk. J Lipid Res 59:1536-1545
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O'Hare, Elizabeth A; Yang, Rongze; Yerges-Armstrong, Laura M et al. (2017) TM6SF2 rs58542926 impacts lipid processing in liver and small intestine. Hepatology 65:1526-1542

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