2021-03-16

Lipids, commonly known as fats, serve essential functions in the body. However, when they are present in excessive amounts or the wrong locations, they can lead to serious diseases. Many people are familiar with the concepts of "bad" and "good" cholesterol, and triglycerides, and how they impact the risk of cardiovascular and lifestyle-related diseases. Gunilla Olivecrona, “grand old lady” at Lipigon, provides insights into the world of lipids and their relevance in Lipigon's projects.

Gunilla Olivecrona, co-founder of Lipigon and a senior professor at the Department of Medical Biosciences at Umeå University, initially pursued a medical career but found her passion for lipids during a chemistry course. She has become an internationally recognized expert in molecular fat metabolism, with over 200 scientific publications in the field of lipid research.

You've dedicated over 45 years to researching lipids. What makes this field so exciting?

"I, and many others around the world, have been researching the properties and functions of the enzyme lipoprotein lipase for many years. It has been challenging but also fantastic. Thanks to rapid technological advancements, a lot of new knowledge has emerged. Today, there is much evidence that increasing lipase activity would significantly reduce the risk of atherosclerosis-related cardiovascular disease, which would improve or even save the lives of many people."

"Currently, only one-third of all cases of cardiovascular disease are prevented, even though patients often succeed in lowering their LDL to levels where it should no longer pose a risk."

Lipids is not a term encountered in everyday conversation. Can you provide more insight into what lipids are?

"Lipids, often referred to as fats, are biological substances that are insoluble in water and require other solvents. This sets lipids apart from proteins and carbohydrates, which are typically highly soluble in water. Lipids are usually found in cell membranes or as stored energy in the form of fat droplets within cells.

In the bloodstream, there are small fat droplets, all covered by proteins and therefore called lipoproteins. Lipoproteins facilitate the transport of lipids between different organs in the body, such as from the intestines where dietary fats are absorbed, or from the liver where various types of fats are synthesized for use throughout the body, including in the muscles.

There are several types of lipids, but in this context, cholesterol and triglycerides are the most well-known. People often talk about "bad cholesterol" LDL (Low-Density Lipoprotein) and "good cholesterol" HDL (High-Density Lipoprotein), based on the fact that cholesterol in LDL is associated with a high risk of heart disease, while cholesterol in HDL protects against heart disease."

What are lipid-related diseases?

"These are diseases that arise because lipids accumulate in the wrong places in the body. Due to the insolubility of lipids, this can lead to problems such as atherosclerosis, or what should actually be called atherosclerofatting, as it is fat that accumulates in the walls of blood vessels. This, in turn, can lead to serious diseases like heart attacks or strokes.

A common term in this context is dyslipidemia, which refers to elevated levels of blood fats or an unfavorable balance between different blood fats. Dyslipidemia often leads to increased levels not only of "bad" LDL cholesterol but also of triglycerides. It is common for individuals with high triglycerides and LDL cholesterol to have lower levels of "good" HDL cholesterol, which further heightens the risk of cardiovascular disease.”

Why is it interesting to research lipids and lipid-related diseases?

"Many people are aware that elevated cholesterol levels are associated with an increased risk of atherosclerosis and cardiovascular diseases such as heart attacks and strokes. There have been effective medications for a long time, like statins, which block the production of cholesterol in the body. Many people take them for preventive purposes or after a heart attack.

However, even if one succeeds in reducing LDL levels through lifestyle changes and medications, it is not guaranteed that the danger is completely gone. Only one-third of all cases of cardiovascular disease are prevented today, even though patients often manage to lower their LDL levels to the point where they should no longer pose a risk."

"Our primary project, Lipisense^®, is expected to have a significant impact on extremely high triglyceride levels but may also have beneficial effects on moderate dyslipidemia caused by factor like age, weight, and type 2 diabetes."

What role do lipids play in various diseases?

“Elevated levels of triglycerides have been observed to increase the risk of atherosclerosis-related cardiovascular diseases, not just high LDL levels. We, and many others, believe that this is due to insufficient or impaired activity of the enzyme lipoprotein lipase (LPL). This enzyme is crucial for breaking down triglycerides, ensuring their rapid removal from the bloodstream to prevent an increased disease risk.”

From our research, we know that lipoprotein lipase is normally produced in excess in the body, meaning there is always potential spare capacity for the enzyme. However, its activity is suppressed by control proteins, one of which is ANGPTL4. When ANGPTL4 binds to lipoprotein lipase, the enzyme loses its ability to break down triglycerides. This is the challenge our main project, Lipisense^®, addresses."

Can you describe the main project, Lipisense^®, in more detail?

"The objective of the project is to enhance the lipoprotein lipase activity by preventing the body from producing ANGPTL4, which we achieve using an antisense oligonucleotide, often referred to as an ASO. Lipisense^® is an ASO, a short DNA/RNA sequence that binds to the RNA of ANGPTL4, preventing the production of the protein.

This approach is anticipated to benefit individuals with extremely high triglyceride levels due to genetic factors, such as familial chylomicronemia syndrome (FCS), and other forms of diseases characterized by elevated triglyceride levels, like severe hypertriglyceridemia (SHTG).

The main problem with high triglyceride levels is that they can lead to acute pancreatitis, a painful and potentially life-threatening condition. The only treatment options available today are strict low-fat diets and a procedure resembling dialysis to remove fat from the blood.

The medication we hope to develop in the Lipisense^® project may also have beneficial effects on common forms of moderate dyslipidemia resulting from factors like age, obesity, and type 2 diabetes, involving elevated levels of triglycerides and LDL cholesterol and lowered HDL cholesterol."

"A medication for liver fat accumulation would be a fantastic tool for treating both rare and common metabolic disorders that might lead to serious illnesses if untreated."

Lipigon's second project focuses on fatty liver and the condition known as lipodystrophy. Tell us more.

“The liver plays a vital role in the body's metabolism, particularly in the processing of fats. Normally, the liver shouldn't store fat for an extended period. If there is an excess of fat, it should be converted into lipoproteins and released into the bloodstream.

However, if these lipoproteins cannot be broken down by lipoprotein lipase in muscles and fat tissue, or if the fat tissue is insulin-resistant and can't store fat, the liver can end up in a challenging situation where fat accumulates as lipid droplets in the liver cells. This leads to what is known as fatty liver, or steatohepatitis, which significantly disrupts the liver's normal control over the body's metabolism.

In the case of lipodystrophy, well-functioning fat tissue is completely or partially missing. This disruption interferes with the liver's typical metabolic functions, causing the entire body to become insulin resistant. Consequently, patients develop type 2 diabetes and blood lipid abnormalities, even if they are notably lean.

The project aims to use gene therapy to give the liver the ability to break down excess fat. The treatment would primarily target individuals with lipodystrophy, as there are currently no effective treatment options for this group.”

The third project is about dyslipidemia. What is it?

“Dyslipidemia refers to general abnormalities in blood lipid levels, as mentioned earlier.

Our third project is similar to the main project, Lipisense^®, and focuses on increasing the activity of lipoprotein lipase in the body. However, in this project, we target common dyslipidemia in large patient groups. The goal is to identify a chemical substance that can be easily administered in tablet form, often in combination with cholesterol-lowering medications.

The treatment's focus is primarily on normalizing triglyceride levels in the blood. This would reduce the well-known residual risk of fat accumulation in blood vessels, leading to atherosclerosis, despite the effective lowering of cholesterol levels. With our proposed treatment, we would also protect the liver and other vital organs from fat accumulation.”

What are your thoughts on the prospects of success in these projects?

"I believe the prospects for success are very promising, even though we are still in the early stages. Regarding lipoprotein lipase, there is no doubt that a drug that can increase the enzyme's activity when it falters for various reasons would be a significant breakthrough. A medication against liver fat accumulation would be a fantastic tool for treating rare and common metabolic disorders that might otherwise lead to serious illnesses."

Read more about Lipigon's projects:

P1 Lipisense
P2 Lipodystrophy
P3 Dyslipidemia
P4 CAP