Wiedmer Therese, Zhao Ji, Li Lilin, Zhou Quansheng, Hevener Andrea, Olefsky Jerrold M, Curtiss Linda K, Sims Peter J
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13296-301. doi: 10.1073/pnas.0405354101. Epub 2004 Aug 24.
The phospholipid scramblases (PLSCR1 to PLSCR4) are a structurally and functionally unique class of proteins, which are products of a tetrad of genes conserved from Caenorhabditis elegans to humans. The best characterized member of this family, PLSCR1, is implicated in the remodeling of the transbilayer distribution of plasma membrane phospholipids but is also required for normal signaling through select growth factor receptors. Mice with targeted deletion of PLSCR1 display perinatal granulocytopenia due to defective response of hematopoietic precursors to granulocyte colony-stimulating factor and stem cell factor. To gain insight into the biologic function of another member of the PLSCR family, we investigated mice with targeted deletion of PLSCR3, a protein that like PLSCR1 is expressed in many blood cells but which, by contrast to PLSCR1, is also highly expressed in fat and muscle. PLSCR3(-/-) mice at 2 months of age displayed aberrant accumulation of abdominal fat when maintained on standard rodent chow, which was accompanied by insulin resistance, glucose intolerance, and dyslipidemia. Primary adipocytes and cultured bone-marrow-derived macrophages from PLSCR3(-/-) mice were engorged with neutral lipid, and adipocytes displayed defective responses to exogenous insulin. Plasma of PLSCR3(-/-) mice was elevated in non-high-density lipoproteins, cholesterol, triglycerides, nonesterified fatty acids, and leptin, whereas adiponectin was low. These data suggest that the expression of PLSCR3 may be required for normal adipocyte and/or macrophage maturation or function and raise the possibility that deletions or mutations affecting the PLSCR3(-/-) gene locus may contribute to the risk for lipid-related disorders in humans.
磷脂翻转酶（PLSCR1至PLSCR4）是一类结构和功能独特的蛋白质，它们是从秀丽隐杆线虫到人类保守的四个基因的产物。该家族中特征最明确的成员PLSCR1参与质膜磷脂跨双层分布的重塑，但也是通过特定生长因子受体进行正常信号传导所必需的。PLSCR1基因靶向缺失的小鼠由于造血前体细胞对粒细胞集落刺激因子和干细胞因子的反应缺陷而出现围产期粒细胞减少。为了深入了解PLSCR家族另一个成员的生物学功能，我们研究了PLSCR3基因靶向缺失的小鼠，PLSCR3蛋白与PLSCR1一样在许多血细胞中表达，但与PLSCR1不同的是，它在脂肪和肌肉中也高度表达。2月龄的PLSCR3(-/-)小鼠在标准啮齿动物饲料喂养下腹部脂肪异常堆积，同时伴有胰岛素抵抗、葡萄糖不耐受和血脂异常。PLSCR3(-/-)小鼠的原代脂肪细胞和培养的骨髓来源巨噬细胞充满中性脂质，脂肪细胞对外源性胰岛素的反应存在缺陷。PLSCR3(-/-)小鼠的血浆中非高密度脂蛋白、胆固醇、甘油三酯、非酯化脂肪酸和瘦素水平升高，而脂联素水平降低。这些数据表明，PLSCR3的表达可能是正常脂肪细胞和/或巨噬细胞成熟或功能所必需的，并增加了影响PLSCR3基因座的缺失或突变可能导致人类脂质相关疾病风险的可能性。
