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More than 500 million people worldwide suffer from cardiovascular diseases; excess fat in blood often plays a role in the development of these diseases. Tallinn University of Technology is developing a method for testing drug candidates for reducing blood fat directly in human plasma, which will speed up the process of finding effective treatments for these diseases.
In Estonia, cardiovascular diseases account for nearly half of all registered deaths. A study conducted in Tallinn found that around a quarter of people have higher than normal blood fat levels. This is important because excessive blood fat plays a role in the development of various diseases, including cardiovascular diseases. Therefore, it is crucial to study how blood fat is broken down and how their levels in the bloodstream can be reduced, writes Natjan-Naatan Seeba, a PhD candidate and junior researcher at Tallinn University of Technology.
The ABCs of fat breakdown
The body uses both fats from food and fats produced by the liver, transporting them to their destinations via the bloodstream, packaged inside of tiny particles known as lipoproteins. Most fats end up in the smallest blood vessels, the capillaries. There, an enzyme known as lipoprotein lipase (LPL) breaks down the fats into smaller pieces called fatty acids. Depending on the tissue, the body either uses these fatty acids for energy in muscles or stores them in fat tissue for future use.
The activity of the enzyme responsible for fat breakdown is regulated by a complex network of proteins. These proteins, found in the bloodstream and in the composition of lipoproteins, can either enhance or inhibit the fat-digesting capacity of LPL. If LPL is not functioning properly, the levels of fat in the blood can also increase. The resulting condition known as hypertriglyceridemia increases the risk of heart disease and pancreatitis.
Therefore, better methods are needed to assess how efficiently blood fat is broken down, to study the mechanisms of this process, and to accelerate the development of drugs that lower blood fat.
A unique approach
The aim of my research is to build upon and apply a unique method developed at Tallinn University of Technology. This method directly examines how lipoprotein lipase breaks down blood fats in human plasma.
To do this, we first put the blood plasma, extracted from people, into a device that measures heat – a calorimeter. We then add LPL and observe the heat released during fat breakdown. Based on the heat released, we can estimate how efficiently LPL breaks down the fat in the person’s blood plasma. As we are working with blood plasma, we replicate the conditions found in the bloodstream, allowing us to observe the overall effect of proteins that influence fat breakdown.
Since people’s blood fat levels can be too high for a variety of reasons, one of the advantages of this method is its personalised approach, using the person’s own blood plasma. Other methods used to measure LPL activity rely on synthetic fat analogues. Additionally, these methods are carried out in environments that are far removed from the conditions typical of the bloodstream.
Searching for new medicines
To date, we have applied the calorimetric method to test a blood fat-lowering drug candidate in the plasma of both healthy persons and those with high blood fat levels. The drug candidate successfully reduced fat levels in both cases, laying the groundwork for its further development.
In addition, we have used this method to elucidate the regulatory effect of the blood protein, albumin, on the structural variability of LPL.
We have also measured enzyme activity in the plasma of various people. For example, we found that fat breakdown is equally effective in the plasma of vegans and omnivores. This implies that a vegan diet decreases the risk of heart disease primarily by lowering cholesterol, with only a minor effect on blood fat breakdown.
In collaboration with Austrian researchers, we have studied patients with lipodystrophy, a condition where the body is unable to produce healthy fat tissue. The study found that the efficiency of fat breakdown measured in the plasma of lipodystrophy patients is lower compared to healthy individuals. This result opens up a new research direction for a better understanding of the disease.
We plan to measure LPL activity in the plasma of more diverse groups of people. We hope to use it to better understand the process of blood fat breakdown and investigate whether the efficiency of fat breakdown measured in plasma could be used to assess disease risk.
We also hope that by understanding blood fat breakdown in more detail and testing drug candidates in blood plasma, we can develop new drugs to lower blood fats. This in turn could reduce the risk of cardiovascular and other related diseases, leading to a healthier society.
Scientific research can be found here:
- Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry
- Lipoprotein Lipase Activity Does Not Differ in the Serum Environment of Vegans and Omnivores
- Apolipoprotein C-II mimetic peptide is an efficient activator of lipoprotein lipase in human plasma as studied by a calorimetric approach
- Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions
- Leptin increases hepatic triglyceride export via a vagal mechanism in humans
Author of this article is Natjan-Naatan Seeba, from Tallinn University of Technology. Editor Jaan-Juhan Oidermaa. Article written for the contest “Science in 3 minutes”.
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