Acetyl-CoA Synthesis in the Skin Is a Key Determinant of Systemic Lipid Homeostasis

    February 2025 in “ Cell Reports ”
    Phuong Nguyen, Michael H.I. Shiue, Nina Kuprasertkul, Pedro Costa‐Pinheiro, Luke Izzo, Laura V. Pinheiro, Hayley C. Affronti, Gabriel B. 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
    This study investigates the role of ATP-citrate lyase (ACLY) in lipid metabolism by using inducible whole-body Acly-knockout mice. The findings reveal that ACLY is essential for skin homeostasis, as its deficiency leads to upregulation of acetyl-CoA synthetase ACSS2. When both Acly and Acss2 are deleted from the skin, it results in significant skin abnormalities, affecting lipid production in the epidermis and sebaceous glands differently. The epidermis experiences a depletion of barrier lipids, while sebaceous glands increase sebum production, partly due to circulating fatty acids and adipose lipolysis. Dietary fat supplementation enhances sebum production and partially mitigates lipoatrophy and skin abnormalities. The study underscores the importance of cytosolic acetyl-CoA synthesis in skin barrier integrity and positions the skin as a crucial organ in systemic lipid regulation.
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