Systematic analyses of lipid mobilization by human lipid transfer proteins
Article Date: 07 January 2026
Article URL: https://www.nature.com/articles/s41586-025-10040-y
Article Image: https://media.springernature.com/full/nature-cms/uploads/product/nature/header-86f1267ea01eccd46b530284be10585e.svg
Summary
This study presents a systematic biochemical, lipidomic and computational characterisation of ~100 human lipid transfer proteins (LTPs). The authors identified bound lipids for roughly half of the LTPs tested, confirmed many known ligands and discovered numerous new LTP–lipid interactions across LTP families. They also tested how LTP gain-of-function alters cellular lipidomes and used structural bioinformatics to reveal determinants of lipid selectivity (head group and acyl-chain preferences). The work shows LTPs commonly bind several lipid classes but preferentially mobilise specific lipid species — notably shorter acyl chains with one or two unsaturations — implying selective mobilisation of lipid subsets. The datasets and supplementary tables provide a resource for further study in different tissues and disease contexts.
Key Points
- Systematic screen of ~100 human LTPs combining in cellulo, in vitro lipidomics and computational analyses.
- Bound lipids were identified for ~50% of LTPs; both known and many previously unreported ligands were found.
- Overexpression (gain-of-function) of LTPs alters cellular abundance of both known and novel ligands, demonstrating functional relevance.
- Structural bioinformatics shows selectivity is driven by both lipid head groups and acyl-chain features (shorter chains, 1–2 unsaturations preferred).
- LTPs often bind multiple lipid classes but mobilise only subsets of species efficiently, implying selective lipid trafficking between organelles.
- The authors provide extensive supplementary data (binding tables, lipidomics, pocket volumes, validation assays) as a community resource.
Content summary
The researchers expressed and purified a large panel of human LTPs in HEK293 cells and performed matched in cellulo and in vitro lipidomic analyses to catalogue LTP-associated lipids. They cross-validated hits, benchmarked binding-pocket volumes against ligand sizes and used fluorescence and biochemical assays for selected domains. Overexpression experiments measured how individual LTPs change cellular lipid species abundance. Computational structural analysis highlighted mechanisms of selectivity, differentiating preferences by head group and acyl-chain composition. The paper emphasises that LTPs have broad but selective binding behaviour and that only particular lipid species (shorter, modestly unsaturated chains) are efficiently mobilised — an important nuance for understanding membrane composition and lipid trafficking in health and disease.
Context and relevance
Why this matters: LTPs maintain organelle-specific membrane composition and many are implicated in human disease. Yet for most human LTPs the actual cargo was unknown. By systematically mapping LTP–lipid interactions and showing functional consequences of LTP activity on cellular lipidomes, this work fills a major gap and provides a searchable dataset for researchers studying membrane biology, lipid metabolism, neurobiology, liver function and pathologies linked to lipid handling. The finding that LTPs selectively mobilise specific lipid species (not entire lipid classes) refines models of inter-organelle lipid traffic and has implications for drug targeting and mechanistic studies.
Why should I read this
Short version: if you care about how cells move lipids around (and why membranes end up with the compositions they do), this is a goldmine. The authors did the hard graft — large-scale experiments, validation and structural checks — so you don’t have to. Read it for the new ligand assignments, the clear rules on chain-length/unsaturation preferences, and the downloadable tables if you want to look up an LTP or design follow-up experiments. Big picture: it changes how we think about which lipid species are actually mobilised by LTPs — and that matters for disease and experimental design.