Most of the energy in our bodies is stored in fat molecules called triglycerides. These lipids are found in our food, and our bodies can produce them as well. When getting your cholesterol levels checked, doctors also have the triglycerides in your blood measured. High levels of triglycerides in the blood are linked to an increased risk of cardiovascular disease. So there are plenty of reasons to uncover the details of how our bodies handle these substances.

Lipid production

Decades ago, scientists already clarified how our cells produce these lipids and which proteins are involved. However, some single-celled organisms appeared to produce triglycerides in additional ways. So why couldn't humans? Oncode researcher Gian-Luca McLelland from Oncode Investigator Thijn Brummelkamp's group at the NKI decided to investigate further.

Detour

This turned out to be an exciting quest, and the researchers are now publishing their results in the scientific journal Nature. They first disabled the well-known production route* in human cells, causing them to stop the production of triglycerides. Through clever puzzling, they then discovered a detour that allowed these cells to keep creating these lipids. They unraveled this detour using Brummelkamp's research method involving haploid cells (see below), which has proven useful many times in the past.

The engine behind this detour turned out to be a protein, its exact function previously unknown. The researchers gave it a fitting name: DIESL**, an abbreviation of its complex biochemical name (see end of article).

Uncharted territory

"This was uncharted territory, and extremely exciting," Brummelkamp explains. "We essentially erased known factors from a cell and observed the effects. It's wonderful when this leads you to find something that is both important and new. I expect that many scientists will be pursuing this exploration further."

This DIESL pathway normally comes equipped with a brake, which might explain why it wasn’t discovered much earlier. McLelland also identified the nature of that brake***, and was able to remove it. And when this brake was removed, cells did indeed start producing triglycerides using their DIESL engines.

Dietary transition

The follow-up question was: how does this work in a living organism? The researchers investigated this as well. "Mice without DIESL grow more slowly than other mice," says McLelland. "This difference emerged precisely during the dietary transition from fatty, nutrient-rich milk to regular food. Together with our colleagues in Groningen, we demonstrated that adult mice without DIESL did not adapt as well as mice with DIESL after a day of fasting."

Cardiovascular diseases

It appears that cells make use of this new pathway during times of food shortage. They utilize fats from within their own cells that they would normally use for something else. "We have always looked at triglycerides from a Western perspective – one in which nutrients are abundant," Brummelkamp says. "Our discovery now highlights the other side of that coin."

Triglycerides have been extensively studied in the context of obesity and cardiovascular diseases. Brummelkamp: "The industry has developed various inhibitors of the classic triglyceride production route to use against obesity, but these haven't been successful due to the side effects."

Tumor cells

What this new discovery will mean in the context of malnutrition, obesity, or human illnesses isn't yet clear, emphasizes Brummelkamp. "I hope that many lipid researchers will soon be investigating the way this new pathway works – and how and when it is relevant in disease and health. I would like to investigate its role in cancer, myself. Tumor cells require more energy than normal cells, and it's often unclear how they obtain it. There's often a shortage of nutrients in a tumor. Could they activate DIESL to gain that energy? This pathway seems particularly suitable for that."

He hopes that this new pathway will be incorporated in the biochemistry textbooks of the future. "You don't often experience moments like these in your career. In true fundamental research, you never know what will result from your work. So discovering something like this is absolutely fantastic."

Turning off genes, one by one

People have thousands of genes, many of which don't have functions that are clear to us. To determine the roles of our genes, Oncode Investigator Thijn Brummelkamp developed a method using haploid cells. These cells contain only one copy of each gene, unlike the regular cells in our bodies that contain two copies. Handling two copies can be challenging in genetic experiments, because changes (mutations) often occur in just one of them. This makes it difficult to observe the effects of these mutations.

Together with other researchers, Brummelkamp has been unraveling processes that are crucial in disease for years, using this versatile method. This is how he uncovered how certain viruses, including the Ebola virus, manage to enter human cells. He also delved into cancer cell resistance against specific therapies and identified proteins that act as brakes on the immune system, which is relevant to cancer immunotherapy. Last year, his team discovered two enzymes that had remained elusive for four decades, and that turned out to be vital for muscle function and brain development. Now his team has unveiled a new pathway through which cells can produce triglycerides.

Read the study in Nature.

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*The DGAT-pathway
** DIESL stands for: DGAT1/2-Independent Enzyme Synthesizing storage Lipids
***TMX1