Pune: Scientists from the Indian Institute of Technology (IIT) Bombay and the Indian Institute of Science Education and Research (IISER) Pune and Kolkata have identified a method to detect and burn excess fat directly in the liver, potentially reducing cholesterol by 50% — at least in the zebrafish used for the experiment.
Breakthrough in Cholesterol Management
Extensive research is still required to determine if the results can be replicated in humans. However, this discovery opens the possibility of a new drug that could help combat high cholesterol, a condition affecting over 25% to 30% of urban Indians, according to studies.
Understanding Liver Function
The liver is the organ where food is converted into fat. This fat is packaged according to the body's needs and sent via the bloodstream. While too much fat can lead to high cholesterol, heart ailments, and other diseases, moderate amounts are essential for healthy bodily functions. Current medications either target reducing cholesterol production or boost the body's ability to clear excess fat.
The liver converts fat into lipid droplets, which act as storage units. Kinesin 1 is a motor protein—a specialized cellular protein that converts chemical energy into mechanical force, enabling the transport of molecules and organelles within cells and driving cellular movements. It ferries these droplets to the periphery of liver cells, where VLDL (very low-density lipoprotein, or bad cholesterol) is synthesized and then carried to various parts of the body via the bloodstream.
The Challenge of Targeting Kinesin 1
“We realized if we disrupt this mechanism, we can prevent the bad cholesterol from entering the blood. However, there was a problem. Motor protein also transports everything else crucial for the body’s essential functions, and not just lipid droplets. So blocking Kinesin 1 entirely was not an option,” said Subham Tripathy, lead author of the paper, which was published last month in the premier scientific journal Proceedings of the National Academy of Sciences.
A post-doctorate at IIT Bombay, Tripathy studied the process for seven years as part of his PhD thesis. The breakthrough came when the team isolated a peptide called Kinesin Tail Domain Peptide (KTDP)—a chain of amino acids, the building blocks of proteins—which is part of the larger motor protein but binds specifically to lipid droplets without affecting other molecules or functions.
Unique Binding Properties of KTDP
KTDP is attracted to lipid droplets alone due to two unique features. “Every cell has some different parts or organelles like nucleus, mitochondria. Most organelles are enclosed by a phospholipid bilayer (two layers) and float in a watery environment. But lipid droplets have fat in the core and are surrounded by a phospholipid monolayer (one layer). We found that within Kinesin 1, it was KTDP that binds differentially to the monolayer of lipid droplets,” said Tripathy.
The researchers then isolated the KTDP peptide from Kinesin 1, cloned it in the lab, introduced it into chicken eggs, and fed them to zebrafish. Zebrafish were used because they are easily grown and have a system similar to the human liver and other organs.
“KTDP—the part we chopped off Kinesin 1—is a peptide that can bind but doesn’t have the capacity to transport anything anymore. The peptide binds to the lipid droplet, preventing the original Kinesin 1 from binding and transporting it,” said Tripathy.
Promising Results in Zebrafish
He said the results were fascinating. “In the zebrafish we fed the extra KTDP, cholesterol and triglyceride levels fell by nearly 50%.”
However, there was a concern: if the fat was not transported out, was it accumulating inside the liver, causing even more damage? “What we found was interesting. The fat content was not changing inside the liver. Even when you take a medicine, it has a lot of side effects. So we were expecting it. But here we saw lipid droplets getting broken down to fatty acids that were taken up by mitochondria (the powerhouse of the cell) and burnt to produce energy,” said Tripathy.
Future Research Directions
Many questions remain unanswered: How is the lipid protein getting broken down? How do proteins selectively recognize the lipid droplet’s monolayer membrane? Can we find new ways to control lipid metabolism and maintain healthy cholesterol levels? Tripathy said the lab would delve into these questions.
His work has already resulted in two research papers and two patent applications, one of which has been published.
Apart from Tripathy and corresponding author Roop Mallik, the team includes Archisman Mahapatra, Ojal Saharan, Hindol Chatterjee, Neelanjana Sengupta, Siddhesh Kamat, and Sreelaja Nair.
