Role of PLSCR3 in Adipogenesis & Adipose Lipid Storage

PLSCR3 在脂肪生成中的作用

• 批准号: 7029339
• 负责人: PETER J SIMS
• 金额: $ 13.87万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029339
• 关键词: adipocytes; adipose tissue; cell differentiation; cell growth regulation; cell line; gene expression; gene mutation; genetic regulation; genetically modified animals; insulin sensitivity /resistance; intracellular transport; laboratory mouse; lipid metabolism; lipid transport; membrane transport proteins; peroxisome proliferator activated receptor; phospholipids; posttranslational modifications; protein metabolism; protein structure function; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Phospholipid Scramblase is a newly-identified gene family, whose proteins (PLSCR1-4) were proposed to mediate accelerated transbilayer movement of plasma membrane phospholipids in cells exposed to elevated intracellular Ca2+. The first identified member of this family, PLSCR1, was shown to be a Ca2+-binding endofacial plasma membrane protein that partitions into cholesterol and sphingomyelin-enriched lipid rafts when palmitoylated, and to traffic into the nucleus to influence gene transcription when not palmitoylated. Cellular expression of PLSCR1 is highly induced by the interferons, as well as by various growth factors, and deletion of PLSCR1 results in defective cell maturation and proliferation in response to these same growth factors. Finally, we have evidence that PLSCR1 plays a central role in receptor signaling and transactivation, through its recruitment of the adapter Shc and the activation of c-Src tyrosine kinase. We have now turned our attention to the role of another member of the PLSCR gene family, PLSCR3. Mice with targeted deletion of PLSCR3 show a marked increase in abdominal fat on a standard (~5% fat) diet, with elevated plasma glucose, cholesterol, triglycerides, and free fatty acids relative to WT controls. These mice also show distinctly abnormal glucose tolerance with evidence of insulin resistance, mimicking Metabolic Syndrome in man (obesity-related insulin resistance with dyslipidemia). Adipocytes from these mice are engorged with lipid and show a marked increase in expression of PPAR? and in genes regulated by this nuclear transcription factor. In this Proposal, we aim (1) To determine whether observed lipid engorgement, insulin resistance, and elevation of PPAR? in PLSCR3-/- adipose represent primary defects of PLSCR3 deficiency in the pre-adipocyte; (2): To determine which properties identified or suspected in the case of PLSCR1 are conserved with respect to PLSCR3; (3) To identify the mechanism by which PLSCR3 - through its activity at the plasma membrane or nucleus - attenuates both PPAR? expression and lipid accumulation in the adipocyte. It is proposed that these experiments will provide new insight into the cellular function of PLSCR3 and into a novel class of genes that appear to influence the accumulation of lipid in adipose tissue and the risk for acquiring the Metabolic Syndrome.

描述（由申请人提供）：磷脂扰乱酶是一个新鉴定的基因家族，其蛋白（PLSCR1-4）被认为可介导暴露于细胞内Ca2+升高的细胞中质膜磷脂的加速跨双层运动。该家族第一个被识别的成员 PLSCR1，被证明是一种结合 Ca2+ 的面质膜蛋白，当棕榈酰化时，它会分解成胆固醇和富含鞘磷脂的脂筏，而当不棕榈酰化时，会进入细胞核以影响基因转录。 PLSCR1 的细胞表达受到干扰素以及各种生长因子的高度诱导，并且 PLSCR1 的缺失会导致响应这些相同生长因子的细胞成熟和增​​殖缺陷。最后，我们有证据表明 PLSCR1 通过招募接头 Shc 和激活 c-Src 酪氨酸激酶，在受体信号传导和反式激活中发挥核心作用。现在我们将注意力转向 PLSCR 基因家族的另一个成员 PLSCR3 的作用。与 WT 对照相比，定向删除 PLSCR3 的小鼠在标准（约 5% 脂肪）饮食中腹部脂肪显着增加，血浆葡萄糖、胆固醇、甘油三酯和游离脂肪酸升高。这些小鼠还表现出明显异常的葡萄糖耐量，并有胰岛素抵抗的证据，类似于人类的代谢综合征（肥胖相关的胰岛素抵抗和血脂异常）。这些小鼠的脂肪细胞充满了脂质，并且 PPAR? 表达显着增加。以及受该核转录因子调节的基因。在本提案中，我们的目标是 (1) 确定是否观察到脂质充血、胰岛素抵抗和 PPAR 升高？ PLSCR3-/-脂肪中的PLSCR3-/-脂肪代表前脂肪细胞中PLSCR3缺乏的主要缺陷； (2)：确定在 PLSCR1 的情况下识别或怀疑的哪些性质相对于 PLSCR3 是保守的； (3) 确定 PLSCR3 通过其在质膜或细胞核的活性减弱 PPAR 的机制？ expression and lipid accumulation in the adipocyte.建议这些实验将为 PLSCR3 的细胞功能和一类新基因提供新的见解，这些基因似乎会影响脂肪组织中脂质的积累以及获得代谢综合征的风险。