Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis
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
Affiliations
Phuong T.T. Nguyen
Department 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, USA
Mia Shiue
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
Nina Kuprasertkul
Department 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, USA
Pedro Costa-Pinheiro
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
Luke T. Izzo
Department 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, USA
Laura V. Pinheiro
Department 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, USA
Hayley A. Affronti
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
Gabriel Gugiu
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
Shivani Ghaisas
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
Joyce Y. Liu
Department 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, USA
Jordan C. Harris
Department 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, USA
Charles W. Bradley
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
John T. Seykora
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
Xiaolu Yang
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
Taku Kambayashi
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Clementina Mesaros
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
Brian C. Capell
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
Kathryn E. Wellen
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
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.
