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Cited by 5Lipid metabolism and biosynthesisLipid metabolism and disordersAutophagy in Disease and Therapy

DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis

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Ismail, Victoria A., Schuetz, Meg, Baker, Zak N., Castillo-Badillo, Jean A., Naismith, Teri V., Pagliarini, David J., Kast, David J.·2025·Journal of Lipid Research
DOI 10.1016/j.jlr.2024.100700PMC PMC11721518
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Abstract

Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYVE1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism.

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Authors
Ismail, V. A., Schuetz, M., Baker, Z. N., Castillo-Badillo, J. A., Naismith, T. V., Pagliarini, D. J., & Kast, D. J.
Affiliations
  • Washington University in St. Louis (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Kast, David J.
ORCID
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2025-01
Volume
66
Issue
1
Pages
100700
ISSN
0022-2275 (ISSN-L)
DOI
10.1016/j.jlr.2024.100700
PMC
PMC11721518
OpenAlex
W4404504785
Cited by
5
References
0
Citations by year
2026: 5
FWCI
0.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Lipid Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Elsa U Pardee Foundation (P20-03924)
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01 GM136925, R35GM131795)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
lipid droplet metabolism, starvation, lipophagy, protein-protein interaction, nutrient sensing, lipid degradation, lipid droplet dynamics
MeSH terms
Acyltransferases, Animals, Humans, Lipase, Lipolysis, Vesicular Transport Proteins, Mice, Lipid Droplets

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