DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis
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 metabol...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002050 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582263544479744 |
|---|---|
| author | Victoria A. Ismail Meg Schuetz Zak N. Baker Jean A. Castillo-Badillo Teri V. Naismith David J. Pagliarini David J. Kast |
| author_facet | Victoria A. Ismail Meg Schuetz Zak N. Baker Jean A. Castillo-Badillo Teri V. Naismith David J. Pagliarini David J. Kast |
| author_sort | Victoria A. Ismail |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ca521fec39fa4870aa735bc2f693e32a |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-ca521fec39fa4870aa735bc2f693e32a2025-01-30T05:12:35ZengElsevierJournal of Lipid Research0022-22752025-01-01661100700DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysisVictoria A. Ismail0Meg Schuetz1Zak N. Baker2Jean A. Castillo-Badillo3Teri V. Naismith4David J. Pagliarini5David J. Kast6Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA; For correspondence: David J. KastLipid 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.http://www.sciencedirect.com/science/article/pii/S0022227524002050ZFYVE1DFCP1ATGLCGI-58ABHD5lipid |
| spellingShingle | Victoria A. Ismail Meg Schuetz Zak N. Baker Jean A. Castillo-Badillo Teri V. Naismith David J. Pagliarini David J. Kast DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis Journal of Lipid Research ZFYVE1 DFCP1 ATGL CGI-58 ABHD5 lipid |
| title | DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis |
| title_full | DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis |
| title_fullStr | DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis |
| title_full_unstemmed | DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis |
| title_short | DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis |
| title_sort | dfcp1 is a regulator of starvation driven atgl mediated lipid droplet lipolysis |
| topic | ZFYVE1 DFCP1 ATGL CGI-58 ABHD5 lipid |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002050 |
| work_keys_str_mv | AT victoriaaismail dfcp1isaregulatorofstarvationdrivenatglmediatedlipiddropletlipolysis AT megschuetz dfcp1isaregulatorofstarvationdrivenatglmediatedlipiddropletlipolysis AT zaknbaker dfcp1isaregulatorofstarvationdrivenatglmediatedlipiddropletlipolysis AT jeanacastillobadillo dfcp1isaregulatorofstarvationdrivenatglmediatedlipiddropletlipolysis AT terivnaismith dfcp1isaregulatorofstarvationdrivenatglmediatedlipiddropletlipolysis AT davidjpagliarini dfcp1isaregulatorofstarvationdrivenatglmediatedlipiddropletlipolysis AT davidjkast dfcp1isaregulatorofstarvationdrivenatglmediatedlipiddropletlipolysis |