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.
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.
|Zeituni, Erin M; Wilson, Meredith H; Zheng, Xiaobin et al. (2016) Endoplasmic Reticulum Lipid Flux Influences Enterocyte Nuclear Morphology and Lipid-dependent Transcriptional Responses. J Biol Chem 291:23804-23816|
|Minchin, James E N; Dahlman, Ingrid; Harvey, Christopher J et al. (2015) Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue. Proc Natl Acad Sci U S A 112:4363-8|
|(2015) Retraction: Visualization of Lipid Metabolism in the Zebrafish Intestine Reveals a Relationship between NPC1L1-Mediated Cholesterol Uptake and Dietary Fatty Acid. Chem Biol 22:1283|
|Otis, Jessica P; Zeituni, Erin M; Thierer, James H et al. (2015) Zebrafish as a model for apolipoprotein biology: comprehensive expression analysis and a role for ApoA-IV in regulating food intake. Dis Model Mech 8:295-309|
|Miyares, Rosa L; de Rezende, Vitor B; Farber, Steven A (2014) Zebrafish yolk lipid processing: a tractable tool for the study of vertebrate lipid transport and metabolism. Dis Model Mech 7:915-27|
|Miyares, Rosa Linda; Stein, Cornelia; Renisch, BjÃ¶rn et al. (2013) Long-chain Acyl-CoA synthetase 4A regulates Smad activity and dorsoventral patterning in the zebrafish embryo. Dev Cell 27:635-47|
|Semova, Ivana; Carten, Juliana D; Stombaugh, Jesse et al. (2012) Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish. Cell Host Microbe 12:277-88|