In February 2026, Nature published a landmark paper: “Systematic analyses of lipid mobilization by human lipid transfer proteins” (Titeca, Chiapparino, Hennrich et al., Nature 651, 511–520). The study mapped, for the first time at scale, which lipids are carried by which of the over 100 known human lipid transfer proteins – a resource that is reshaping how the field thinks about membrane biology and lipid-linked disease. Behind this achievement is the group of Anne-Claude Gavin, currently at the University of Geneva, Switzerland who spent years developing the methods, building the datasets, and finding the right partners to make it possible. One of those partnerships began with a Lipotype Excellence Award in 2019. We sat down with her to hear how it all came together.
What are Lipid transfer proteins?
Lipid transfer proteins (LTPs) are molecular machines that extract specific lipids from one membrane and deliver them to another in a selective and directional way. There are more than 130 of them in human cells, and they are essential for maintaining the distinct lipid compositions of organelles.
Olya: Your lab’s interest in LTPs grew out of a much broader question about metabolite-protein interactions. Can you take us back to how it started?
Anne-Claude: We originally had a very broad vision. Biology is made of interactions – biomolecules that interact with each other. We understand quite well how proteins interact with other proteins, how nucleic acids interact with proteins. But we barely understand how metabolites interact with all those other biomolecules. Metabolites have always been considered as end products, the output of the system. But we never really thought about them as regulators. And I thought: we should start now to chart protein-metabolite interactions beyond the catalytic ones.
We started with lipids because we thought they were going to be simple [laughs]. Simple in the sense that everybody already agreed that lipids need to be localized. Not all membranes are the same. And LTPs were an obvious entry point: proteins that clearly had to interact with lipids. Simple, right? Well.
Olya: And what made this such a hard problem to crack?
Anne-Claude: The mystery is really at the molecular level. For enzymes, we have a good understanding – how they meet their substrate, how the catalytic step is driven, what cofactors are required. But for lipid transporters, it is absolutely mysterious. How do you convince a hydrophobic lipid, in a hydrophobic membrane, to jump into the hydrophobic core of a protein? And on top of that, it has to be specific as not just any lipid goes in there. And then there is directionality: you take the lipid from one membrane to the other, and you don’t bring it backwards. We simply don’t understand how that works for the majority of transporters.
Olya: That sounds like an enormous experimental challenge. How did you build the approach to study all of them systematically?
Anne-Claude: We spent quite some time developing biochemical methods to measure protein–lipid interactions. We started in yeast, because we thought that knew the cargoes for those 14 transporters and we could check that our protocol was working in a real system. And then we made a surprising discovery: a member of the oxysterol-binding family that was supposed to bind sterol actually binds phosphatidylserine. That kept us in yeast much longer than expected. Then we moved to human cells, and that is when the lipidomics became a serious challenge.
What are phosphatidylserines?
Phosphatidyl-serines are essential membrane components and contribute to the organization of protein complexes on the cytosolic side of the membrane, thus facilitating signaling activities.
Olya: That is where Lipotype came in?
Anne-Claude: Exactly. We had done lipidomics in the group, and we knew how to do it. But to do it at the level of the entire lipidome – that is really an expertise we did not have. We had expertise in affinity purification mass spectrometry (AP-MS) with relatively simple lipidomes, where you purify your compound and filter out the background. But whole-cell lipidomic analysis is a different level entirely. And I did not want to reinvent the wheel when there was a company like Lipotype, who had all this expertise since decades. When I saw the Lipid Excellence Award prize announcement, I thought: that is where we could really team up, and this award would make a difference.
Olya: You had not worked with Lipotype before. Was the application process difficult?
Anne-Claude: Not at all – that is also the beauty of this award. It is bureaucratic-light. There is not much bureaucracy, so the money really goes to the science. Every cent goes to the research.
Olya: And once the collaboration started, how did it work in practice?
Anne-Claude: We were very well taken care of. There were a lot of online meetings and emails to decide on the experimental design, and that interface between the two teams is really key. This is where a project can succeed or fail. My PhD student, Larissa Van Heck, took the lead on that, and she could almost manage it independently. She was really well mentored by the Lipotype team. The communication was always very clear and smooth.
Olya: What specifically did the lipidomics data contribute to the paper?
Anne-Claude: It became one of our validation pillars. The logic was: if a transporter really does carry specific lipids to a specific organelle, then if you overexpress that transporter – if you push the transport – you should see a measurable change in lipid composition at the destination.
For a protein called STARD11, for example, we had found ceramide (the known cargo), phosphatidylcholine and triacylglycerol associated with it in our screen. When we did the lipidomics with Lipotype on the gain-of-function cells, we found a decrease in phosphatidylcholine and triacylglycerol. So, we knew that those two lipids we had found associated with STARD11 were indeed being functionally mobilized. That was a really cool validation.
What are phosphatidylcholines?
Phosphatidylcholines serve as key building blocks for biological membranes, and they play an important role in plasma lipoproteins, the biochemical structures to transport lipids in blood plasma.
Olya: Now that the paper is out, what does this resource mean for the field going forward?
Anne-Claude: I think we have brought some systems biology thinking to the lipid field. The idea is that if you want to understand lipid transport, it is not just a matter of understanding one transporter, You need to understand them as a cohort, working together as a whole. And now that we know the cargo and cofactors for many of them, we can start doing structural analyses, one at a time. We can couple this to CRISPR screens, to perturbation experiments, to different cell types. It is a blueprint for a lot of follow-up work.
Of course, it is just a first draft. There are still many LTPs we could not fully characterize, and the lipidome itself still has gaps. But that is the exciting part – we know what to do next.
What lipid are you?
Many lipid transfer proteins (LTPs) might not be fully characterized yet but you can be!
*Anne-Claude Gavin is a professor of cell biology at the University of Geneva, Switzerland. The Lipotype Excellence Award was granted by Lipotype to support researchers whose work stands to benefit from access to professional lipidomics expertise. The 2019 award contributed to the lipidomic validation that is part of the Nature 2026 publication.
