Fatty finding fuels scientists’ understanding of human cells

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? Gian-Luca McLelland from Thijn Brummelkamp's research group at the Netherlands Cancer Institute 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 Thijn'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.

Uncharted territory

"This was uncharted territory, and extremely exciting," Thijn 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."

Cells were stained for DNA (blue) and triglycerides (green). Cells lacking TMX1 accumulate a high amount of triglycerides (left panel). DIESL is needed for the accumulation of triglycerides when TMX1 is inactivated (right panel).

This DIESL pathway normally comes equipped with a brake, which might explain why it wasn’t discovered much earlier. Gian-Luca 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 Gian-Luca. "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 disease

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," Thijn says. "Our discovery now highlights the other side of that coin."

Triglycerides have been extensively studied in the context of obesity and cardiovascular diseases. Thijn: "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, Thijn emphasizes. "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."

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

This study was financially supported by Oncode Institute