Phospholipid Scramblase 4 (PLSCR4) Regulates Adipocyte Differentiation via PIP3-Mediated AKT Activation.

Abstract

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 PTEN-associated adipose-tissue overgrowth and lipoma formation.

• Authors: Lisa A G Barth, Michèle Nebe, Hermann Kalwa, Akhil Velluva, Stephanie Kehr, Florentien Kolbig, Patricia Prabutzki, Wieland Kiess, Diana Le Duc, Antje Garten, Anna S Kirstein
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 17 (Aug 29 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36077184 (Publication Type: Journal Article)

Chemical References

• PLSCR4 protein, human
• Phosphatidylinositols
• Phospholipid Transfer Proteins
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase

Topics

• Adipocytes (metabolism)
• Animals
• Humans
• Mice
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphatidylinositols
• Phospholipid Transfer Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)