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

acetyl-CoA ATP-citrate lyase ACLY acetyl-CoA synthetase ACSS2 lipid metabolism epidermis sebaceous glands barrier lipids sebum production fatty acids adipose lipolysis cytosolic acetyl-CoA synthesis skin barrier integrity skin homeostasis lipid production skin abnormalities dietary fat supplementation

Studysummary In this study, inducible whole-body Acly-knockout mice revealed that ACLY is essential for skin homeostasis, as its deficiency led to increased sebum production and skin abnormalities, indicating a vital role for cytosolic acetyl-CoA synthesis in preserving skin barrier integrity and systemic lipid regulation.

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The study examines the role of acetyl-CoA synthesis in the skin and its effect on systemic lipid homeostasis using Acly-knockout mice. The absence of ACLY and ACSS2 enzymes leads to skin abnormalities, fat loss, and increased sebum production, with exacerbated effects when both enzymes are missing. This disruption affects epidermal lipid composition, reducing crucial triglycerides and ceramides, yet sebum production increases due to circulating fatty acids. Olive oil supplementation partially mitigates these effects but does not restore the lipid profile. The findings emphasize the skin's critical role in lipid metabolism and its systemic implications, highlighting the need for further research into skin-specific metabolic interactions.

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