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Phospholipid Scramblase 4 (PLSCR4) Regulates Adipocyte Differentiation via PIP3-Mediated AKT ActivationA. G. Barth, Lisa, Nebe, Michèle, Kalwa, Hermann, Velluva, Akhil, Kehr, Stephanie, Kolbig, Florentien, Prabutzki, Patricia, Kiess, Wieland, Le Duc, Diana, Garten, Antje, S. Kirstein, Anna 05 December 2023 (has links)
Phospholipid scramblase 4 (PLSCR4) is a member of a conserved enzyme family with
high relevance for the remodeling of phospholipid distribution in the plasma membrane and the
regulation of cellular signaling. While PLSCR1 and -3 are involved in the regulation of adipose-tissue
expansion, the role of PLSCR4 is so far unknown. PLSCR4 is significantly downregulated in an
adipose-progenitor-cell model of deficiency for phosphatase and tensin homolog (PTEN). PTEN
acts as a tumor suppressor and antagonist of the growth and survival signaling phosphoinositide
3-kinase (PI3K)/AKT cascade by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (PIP3).
Patients with PTEN germline deletion frequently develop lipomas. The underlying mechanism for
this aberrant adipose-tissue growth is incompletely understood. PLSCR4 is most highly expressed in
human adipose tissue, compared with other phospholipid scramblases, suggesting a specific role
of PLSCR4 in adipose-tissue biology. In cell and mouse models of lipid accumulation, we found
PLSCR4 to be downregulated. We observed increased adipogenesis in PLSCR4-knockdown adipose
progenitor cells, while PLSCR4 overexpression attenuated lipid accumulation. PLSCR4 knockdown
was associated with increased PIP3 levels and the activation of AKT. Our results indicated that
PLSCR4 is a regulator of PI3K/AKT signaling and adipogenesis and may play a role in PTENassociated adipose-tissue overgrowth and lipoma formation.
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