Baltimore, MD — Metabolic syndrome affects about one-third of the US population and is associated with dyslipidemia, a lipid imbalance that underlies cardiovascular disease and many other serious conditions.

Lipids, such as fats, oils, and cholesterol, are waxy compounds that serve as both energy reservoirs and cellular building blocks. However, these molecules are difficult to dissolve in biological fluids, which are primarily made up of water. (You might have heard … oil and water do not mix!) This “water-aversion,” or hydrophobicity, poses a problem to lipid-handling organs, such as the intestine, whose job is to absorb dietary lipids and transport them throughout the body.

To circumvent water-aversion, lipids are packaged with a protective coat, forming particles called ApoB-lipoproteins. These compounds of lipid and protein allow lipids to be shuttled from where they are absorbed to places where they are needed. When unregulated, however, excess ApoB-lipoproteins can lead to a dangerous buildup called plaque that stiffens artery walls and makes it more difficult for the heart to pump blood—which can eventually lead to heart attack.

The mechanisms that underlie the regulation of ApoB-lipoproteins are poorly understood, but over the past several years, the Farber Lab at Carnegie’s Department of Embryology has had great success in researching lipoprotein biology in zebrafish larvae, leading to a better understanding of the critical players in lipoprotein metabolism. 

“ApoB lipoprotein metabolism and its associated pathologies have been difficult to investigate due to the limitations of cell culture models for studying multi-organ phenomena,” says Farber Lab postdoctoral researcher McKenna Feltes, “as well as the relative inaccessibility of mammalian models to visualize lipoprotein dynamics at the subcellular level.” 

Zebrafish present a unique solution to these challenges. In their embryonic and larval stages, zebrafish robustly produce ApoB-containing lipoproteins, are amenable to genetic manipulation, and are optically clear—enabling live imaging on the subcellular to whole-organism scale.

While the genes studied by the Farber Lab play very different roles in controlling ApoB-lipoprotein metabolism, they share a common feature when mutated: In each case, the fish’s yolk sac becomes opaque due to excess lipid build-up, a phenomenon the lab refers to as "dark yolk."  

 

McKenna Feltes tends to tanks of mutagenized zebrafish that she screened for “dark yolk” in the fall of 2021.

 
With this in mind, Feltes has designed a genetic approach to identify additional genes linked to lipoprotein biogenesis. By starting with a search through randomly mutated zebrafish for "dark yolk," she hopes to uncover unanticipated genes that regulate lipoprotein biology. 
 
In 2021, the National Institutes of Health recognized Feltes’s foresight with its Ruth L. Kirschstein Postdoctoral Individual National Research Service Award.
 
To read more about Carnegie’s work related to metabolic disease, click here.