Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis
Summary: ATP-citrate lyase (ACLY) generates cytosolic acetyl-coenzyme A (acetyl-CoA) for lipid synthesis and is a promising therapeutic target in diseases with altered lipid metabolism. Here, we developed inducible whole-body Acly-knockout mice to determine the requirement for ACLY in normal tissue...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000555 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823859407305310208 |
|---|---|
| author | Phuong T.T. Nguyen Mia Shiue Nina Kuprasertkul Pedro Costa-Pinheiro Luke T. Izzo Laura V. Pinheiro Hayley A. Affronti Gabriel Gugiu Shivani Ghaisas Joyce Y. Liu Jordan C. Harris Charles W. Bradley John T. Seykora Xiaolu Yang Taku Kambayashi Clementina Mesaros Brian C. Capell Kathryn E. Wellen |
| author_facet | Phuong T.T. Nguyen Mia Shiue Nina Kuprasertkul Pedro Costa-Pinheiro Luke T. Izzo Laura V. Pinheiro Hayley A. Affronti Gabriel Gugiu Shivani Ghaisas Joyce Y. Liu Jordan C. Harris Charles W. Bradley John T. Seykora Xiaolu Yang Taku Kambayashi Clementina Mesaros Brian C. Capell Kathryn E. Wellen |
| author_sort | Phuong T.T. Nguyen |
| collection | DOAJ |
| description | Summary: ATP-citrate lyase (ACLY) generates cytosolic acetyl-coenzyme A (acetyl-CoA) for lipid synthesis and is a promising therapeutic target in diseases with altered lipid metabolism. Here, we developed inducible whole-body Acly-knockout mice to determine the requirement for ACLY in normal tissue functions, uncovering its crucial role in skin homeostasis. ACLY-deficient skin upregulates the acetyl-CoA synthetase ACSS2; deletion of both Acly and Acss2 from the skin exacerbates skin abnormalities, with differential effects on two major lipid-producing skin compartments. While the epidermis is depleted of barrier lipids, the sebaceous glands increase production of sebum, supplied at least in part by circulating fatty acids and coinciding with adipose lipolysis and fat depletion. Dietary fat supplementation further boosts sebum production and partially rescues both the lipoatrophy and the aberrant skin phenotypes. The data establish a critical role for cytosolic acetyl-CoA synthesis in maintaining skin barrier integrity and highlight the skin as a key organ in systemic lipid regulation. |
| format | Article |
| id | doaj-art-8666369faff54c7db30a8b36524b1016 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-8666369faff54c7db30a8b36524b10162025-02-11T04:34:45ZengElsevierCell Reports2211-12472025-02-01442115284Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasisPhuong T.T. Nguyen0Mia Shiue1Nina Kuprasertkul2Pedro Costa-Pinheiro3Luke T. Izzo4Laura V. Pinheiro5Hayley A. Affronti6Gabriel Gugiu7Shivani Ghaisas8Joyce Y. Liu9Jordan C. Harris10Charles W. Bradley11John T. Seykora12Xiaolu Yang13Taku Kambayashi14Clementina Mesaros15Brian C. Capell16Kathryn E. Wellen17Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USADepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA, USADepartment of Dermatology, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA, USADepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Dermatology, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USADepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USADepartment of Dermatology, University of Pennsylvania, Philadelphia, PA, USADepartment of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Corresponding authorSummary: ATP-citrate lyase (ACLY) generates cytosolic acetyl-coenzyme A (acetyl-CoA) for lipid synthesis and is a promising therapeutic target in diseases with altered lipid metabolism. Here, we developed inducible whole-body Acly-knockout mice to determine the requirement for ACLY in normal tissue functions, uncovering its crucial role in skin homeostasis. ACLY-deficient skin upregulates the acetyl-CoA synthetase ACSS2; deletion of both Acly and Acss2 from the skin exacerbates skin abnormalities, with differential effects on two major lipid-producing skin compartments. While the epidermis is depleted of barrier lipids, the sebaceous glands increase production of sebum, supplied at least in part by circulating fatty acids and coinciding with adipose lipolysis and fat depletion. Dietary fat supplementation further boosts sebum production and partially rescues both the lipoatrophy and the aberrant skin phenotypes. The data establish a critical role for cytosolic acetyl-CoA synthesis in maintaining skin barrier integrity and highlight the skin as a key organ in systemic lipid regulation.http://www.sciencedirect.com/science/article/pii/S2211124725000555CP: Metabolism |
| spellingShingle | Phuong T.T. Nguyen Mia Shiue Nina Kuprasertkul Pedro Costa-Pinheiro Luke T. Izzo Laura V. Pinheiro Hayley A. Affronti Gabriel Gugiu Shivani Ghaisas Joyce Y. Liu Jordan C. Harris Charles W. Bradley John T. Seykora Xiaolu Yang Taku Kambayashi Clementina Mesaros Brian C. Capell Kathryn E. Wellen Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis Cell Reports CP: Metabolism |
| title | Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis |
| title_full | Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis |
| title_fullStr | Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis |
| title_full_unstemmed | Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis |
| title_short | Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis |
| title_sort | acetyl coa synthesis in the skin is a key determinant of systemic lipid homeostasis |
| topic | CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000555 |
| work_keys_str_mv | AT phuongttnguyen acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT miashiue acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT ninakuprasertkul acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT pedrocostapinheiro acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT luketizzo acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT lauravpinheiro acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT hayleyaaffronti acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT gabrielgugiu acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT shivanighaisas acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT joyceyliu acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT jordancharris acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT charleswbradley acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT johntseykora acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT xiaoluyang acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT takukambayashi acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT clementinamesaros acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT brianccapell acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis AT kathrynewellen acetylcoasynthesisintheskinisakeydeterminantofsystemiclipidhomeostasis |