February, 2022 — Microsomal triglyceride transfer protein (MTP) is a major cellular protein that plays a significant role in transferring fat and cholesterol molecules, also known as lipids, throughout the body. Drugs that target MTP could potentially treat heart disease and many other metabolic conditions, including diabetes and fatty liver disease, all of which stem from underlying defects in lipid metabolism.
MTP is part of an intracellular molecular machine essential for forming lipoproteins, a particle comprised of lipid and protein, which can sometimes turn into “bad cholesterol” by embedding themselves into the sides of blood vessels. Called plaque, these deposits build up to stiffen artery walls and make it more difficult for the heart to pump blood, leading to heart disease and an increased risk of heart attack or stroke.
While several drugs have been developed that block the function of MTP and strongly reduce harmful cholesterol levels, they also completely break the cell’s ability to make lipoproteins, resulting in adverse side effects.
No drug has yet been developed specifically to break only part of the function of MTP. However, promising data recently published by the Farber Lab at Carnegie’s Department of Embryology provides evidence that selective restriction of MTP’s triglyceride transfer function may be a viable therapeutic approach to treat lipid disorders — without causing the negative side effects associated with total MTP inhibition.
Lishann Ingram, a member of the Farber Lab, has been working for two years to identify compounds that specifically block the triglyceride transfer activity of MTP but retain other functions, as well as to study how these compounds alter general lipid processing in zebrafish. With help from a grant from The National Institute of Diabetes and Digestive and Kidney Diseases, which she won in 2020, Ingram and her team have already identified hundreds of compounds that lower cholesterol levels in larval fish.
Lishann Ingram uses a robotics system to screen for compounds that change cholesterol levels in larval zebrafish. The robot, located in the Mumm Lab at Johns Hopkins University, automates the loading of live zebrafish larvae, test compounds, and LipoGlo components into 96-well plates.
“I am focusing on compounds that produce a modest reduction in lipoprotein number and size consistent with what we observe in zebrafish when only the triglyceride transfer activity of MTP is inhibited,” explains Ingram. “Specifically, I’m looking for compounds that lower plasma triglycerides and do not produce intestinal lipid retention.”
The team recently finished the large-scale drug screen of 10,000 compounds; a daunting task made easier with the help of a robotics system and with LipoGlo, a state-of-the-art zebrafish model that “tags” bad cholesterol in living fish with a glowing enzyme. Developed by Carnegie’s James Thierer and Steven Farber, LipoGlo allows researchers to observe lipoprotein levels, size, and distribution in living fish in real-time.
Stay tuned for updates on this exciting work!