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.
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."
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.”
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."
** DIESL stands for: DGAT1/2-Independent Enzyme Synthesizing storage Lipids
This study was financially supported by Oncode Institute