Role of PLSCR3 in Adipogenesis & Adipose Lipid Storage

PLSCR3 在脂肪形成中的作用

• 批准号: 7123418
• 负责人: PETER J SIMS
• 金额: $ 24.25万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123418
• 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，其蛋白质（PLSCR 1 -4）被认为介导暴露于升高的细胞内Ca 2+的细胞中质膜磷脂的加速跨双层运动。该家族的第一个成员PLSCR 1被证明是一种Ca 2+结合的内面质膜蛋白，当棕榈酰化时，其分配到胆固醇和鞘磷脂富集的脂筏中，并且当不棕榈酰化时，其进入细胞核以影响基因转录。PLSCR 1的细胞表达由干扰素以及各种生长因子高度诱导，并且PLSCR 1的缺失导致响应于这些相同生长因子的缺陷性细胞成熟和增殖。最后，我们有证据表明，PLSCR 1在受体信号转导和反式激活中发挥着重要作用，通过其招聘的适配器Shc和激活c-Src酪氨酸激酶。我们现在已经将注意力转向PLSCR基因家族的另一个成员PLSCR 3的作用。PLSCR 3靶向缺失的小鼠在标准（~5%脂肪）饮食下显示腹部脂肪显著增加，相对于WT对照，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伴血脂异常）。这些小鼠的脂肪细胞充满了脂质，并显示出显着增加表达的过氧化物酶体增殖物激活受体？以及受这种核转录因子调控的基因。在本研究中，我们的目的是（1）确定是否观察到的脂质充盈，胰岛素抵抗，和升高的过氧化物酶体增殖物激活物受体？（2）：确定在PLSCR 1的情况下鉴定或怀疑的哪些性质相对于PLSCR 3是保守的; (3)为了确定PLSCR 3-通过其在质膜或细胞核的活性-减弱两个PPAR？表达和脂肪细胞中的脂质积累。有人提出，这些实验将提供新的见解PLSCR 3的细胞功能和一类新的基因，似乎影响脂肪组织中的脂质积累和获得代谢综合征的风险。