Organelle associations and metabolic rewiring of size-defined hepatic lipid droplets

Abstract

Lipid droplet (LD) size is a key determinant of hepatic lipid metabolism, yet the molecular programming routing size-defined subpopulations to distinct fates remains unclear. Here we show that a fractionation workflow resolves hepatic LDs by size and organelle association, defining a high-confidence intrinsic LD proteome. Moreover, comparative proteomics of fasted livers reveals a clear ‘division of labor’: Large LDs (L-LDs) function as specialized mitochondrion-coupled ‘putative fueling hubs’, whereas small LDs (S-LDs) serve as lysosome-coupled ‘putative trafficking and turnover hubs’. This interaction map is highly plastic; metabolic stress (fasting or steatosis) triggers a programmatic remodeling where lysosomal machinery is inducibly recruited to S-LDs. Crucially, in vivo stress recruits mitochondria to both pools, supporting a ‘parallel programs’ model where S-LD-associated mitochondria are hypothesized to power the energy-intensive degradative machinery. These findings establish that metabolic state leverages LD size to direct organelle partnerships, nominating the small-LD lysosomal axis as a critical regulatory node in metabolic-associated fatty liver disease (MAFLD).

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BibTeX RIS

BibTeX

@article{liao2026organelle,
  title = {{Organelle associations and metabolic rewiring of size-defined hepatic lipid droplets}},
  author = {Qiumin Liao and Xiaochuan Fu and Yang Wang and Yilu Xu and Zhen Cao and Yusong Wang and Bin Pan and Jifeng Wang and Pingsheng Liu and Zhiyun Yang and Shuyan Zhang},
  journal = {Communications Biology},
  year = {2026},
  month = oct,
  doi = {10.1038/s42003-026-11185-w},
  url = {https://www.nature.com/articles/s42003-026-11185-w},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Organelle associations and metabolic rewiring of size-defined hepatic lipid droplets
AU  - Qiumin Liao
AU  - Xiaochuan Fu
AU  - Yang Wang
AU  - Yilu Xu
AU  - Zhen Cao
AU  - Yusong Wang
AU  - Bin Pan
AU  - Jifeng Wang
AU  - Pingsheng Liu
AU  - Zhiyun Yang
AU  - Shuyan Zhang
PY  - 2026
DA  - 2026/10/18
JO  - Communications Biology
DO  - 10.1038/s42003-026-11185-w
UR  - https://www.nature.com/articles/s42003-026-11185-w
AB  - Lipid droplet (LD) size is a key determinant of hepatic lipid metabolism, yet the molecular programming routing size-defined subpopulations to distinct fates remains unclear. Here we show that a fractionation workflow resolves hepatic LDs by size and organelle association, defining a high-confidence intrinsic LD proteome. Moreover, comparative proteomics of fasted livers reveals a clear ‘division of labor’: Large LDs (L-LDs) function as specialized mitochondrion-coupled ‘putative fueling hubs’, whereas small LDs (S-LDs) serve as lysosome-coupled ‘putative trafficking and turnover hubs’. This interaction map is highly plastic; metabolic stress (fasting or steatosis) triggers a programmatic remodeling where lysosomal machinery is inducibly recruited to S-LDs. Crucially, in vivo stress recruits mitochondria to both pools, supporting a ‘parallel programs’ model where S-LD-associated mitochondria are hypothesized to power the energy-intensive degradative machinery. These findings establish that metabolic state leverages LD size to direct organelle partnerships, nominating the small-LD lysosomal axis as a critical regulatory node in metabolic-associated fatty liver disease (MAFLD).
SN  - 2399-3642
ER  -

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