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磷脂翻转酶 4（PLSCR4）通过 PIP3 介导的 AKT 激活调节脂肪细胞分化。

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

机构信息

University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, 04103 Leipzig, Germany.

Institute of Pharmacology, Pharmacy and Toxicology, Leipzig University, 04107 Leipzig, Germany.

出版信息

Int J Mol Sci. 2022 Aug 29;23(17):9787. doi: 10.3390/ijms23179787.

DOI:10.3390/ijms23179787
PMID:36077184
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9456373/
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.

摘要

磷脂翻转酶 4（PLSCR4）是一种保守的酶家族成员，与质膜中磷脂分布的重塑和细胞信号转导的调节密切相关。虽然 PLSCR1 和 -3 参与了脂肪组织扩张的调节，但 PLSCR4 的作用迄今尚不清楚。在磷酸酶和张力蛋白同源物（PTEN）缺乏的脂肪祖细胞模型中，PLSCR4 显著下调。PTEN 作为肿瘤抑制因子，通过去磷酸化磷脂酰肌醇-3,4,5-三磷酸（PIP3）拮抗生长和存活信号磷酸肌醇 3-激酶（PI3K）/AKT 级联反应。PTEN 种系缺失的患者常发生脂肪瘤。这种异常脂肪组织生长的潜在机制尚不完全清楚。与其他磷脂翻转酶相比，PLSCR4 在人脂肪组织中表达最高，这表明 PLSCR4 在脂肪组织生物学中具有特定的作用。在细胞和脂质积累的小鼠模型中，我们发现 PLSCR4 下调。我们观察到 PLSCR4 敲低的脂肪祖细胞中脂肪生成增加，而 PLSCR4 过表达则减弱了脂质积累。PLSCR4 敲低与 PIP3 水平升高和 AKT 激活有关。我们的研究结果表明，PLSCR4 是 PI3K/AKT 信号转导和脂肪生成的调节剂，可能在与 PTEN 相关的脂肪组织过度生长和脂肪瘤形成中发挥作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1f5/9456373/bc689fd67116/ijms-23-09787-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1f5/9456373/4d83144b8c20/ijms-23-09787-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1f5/9456373/bc689fd67116/ijms-23-09787-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1f5/9456373/4d83144b8c20/ijms-23-09787-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1f5/9456373/ee4fd366a5b1/ijms-23-09787-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1f5/9456373/cec3ce204456/ijms-23-09787-g003.jpg
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