Molecular Physiology of Liver Fatty Acid Transporters

肝脏脂肪酸转运蛋白的分子生理学

• 批准号: 7046691
• 负责人: Andreas Stahl
• 金额: $ 29.3万
• 依托单位: PALO ALTO MEDICAL FOUNDATION RES INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046691
• 关键词: cell line; cell morphology; fatty acid transport; gene expression; genetically modified animals; insulin sensitivity /resistance; laboratory mouse; liver cells; liver metabolism; long chain fatty acid; noninsulin dependent diabetes mellitus; protein localization; protein structure function; transport proteins; triglycerides

DESCRIPTION (provided by applicant): The liver is a central organ for coordinating much of metabolism and has a large capacity for fatty acid uptake. Considerable evidence has accumulated to show that in addition to a diffusional component, the intestine, heart, adipose tissue, and the liver express a saturable and specific long-chain fatty acid transport system. Identifying the postulated liver fatty acid transporter is of considerable importance, since both increased and decreased hepatic LCFA uptake have been implicated in diseases such as type-2 diabetes and acute liver failure. Investigators have found several membrane proteins that increase the uptake of LCFAs when overexpressed in cultured mammalian cells. The most prominent and best characterized of these are FAT/CD36 and fatty acid transport proteins (FATPs, solute carrier family 27). However, neither the better studied FATPs, FATP1 and -4, nor CD36 are expressed at appreciable levels in the liver. Therefore, we have identified FATPs that are expressed in the liver and have characterized their contribution to protein-mediated LCFA uptake and general energy homeostasis. We have identified two FATP family members, FATP5 and -2, as possible candidates for this role. FATP2 is expressed in liver and kidney, while FATP5 expression is liver-specific. The purpose of this proposal is to determine the contribution of FATP5 to hepatic fatty acid uptake. To accomplish this, we will determine the localization and regulation of FATP5 in the liver and generate animal models for loss and gain of FATP5 function. To this end, we have generated FATP5 null mice, which show reduced hepatic fatty acid uptake and diminished liver triglyceride content. We will use this unique model system to explore the role of liver LCFA uptake for energy homeostasis and the etiology of diseases, particularly of type-2 diabetes. Excessive liver TG accumulation is a well-described feature of the "metabolic syndrome" and may, in part, be responsible for insulin resistance and increased glucose levels. To evaluate FATP5 as a potential target for therapeutic intervention, we will test whether FAT5 null animals show reduced lipid accumulation, and increased insulin sensitivity in dietary and genetically induced models of diabetes. We will also test the hypothesis that the converse is true, by generating FATP5 transgenic mice, which may have increased liver LCFA uptake.

描述(申请人提供)：肝脏是协调大部分新陈代谢的中心器官，有很大的吸收脂肪酸的能力。大量的证据表明，除了扩散成分外，肠道、心脏、脂肪组织和肝脏还表达一种饱和的和特定的长链脂肪酸运输系统。确定假定的肝脏脂肪酸转运体是相当重要的，因为肝脏LCFA摄取增加和减少都与2型糖尿病和急性肝功能衰竭等疾病有关。研究人员发现，当在培养的哺乳动物细胞中过度表达时，几种膜蛋白可以增加对LCFAs的摄取。其中最突出和最具特点的是脂肪/CD36和脂肪酸运输蛋白(FATPs，溶质载体家族27)。然而，无论是研究较好的FATP，FATP1和-4，还是CD36在肝脏中都没有明显的表达水平。因此，我们已经确定了在肝脏中表达的FATP，并表征了它们对蛋白质介导的LCFA摄取和总能量平衡的贡献。我们已经确定FATP家族的两个成员FATP5和FATP2可能担任这一角色。FATP2在肝脏和肾脏中表达，而FATP5在肝脏中特异表达。这项建议的目的是确定FATP5对肝脏脂肪酸摄取的贡献。为此，我们将确定FATP5在肝脏中的定位和调节，并建立FATP5功能丧失和获得的动物模型。为此，我们培育了FATP5缺失的小鼠，这些小鼠表现出肝脏脂肪酸摄取减少和肝脏甘油三酯含量减少。我们将使用这个独特的模型系统来探索肝脏LCFA摄取在能量平衡和疾病病因中的作用，特别是2型糖尿病。肝脏甘油三酯过多积聚是“代谢综合征”的一个典型特征，可能是胰岛素抵抗和血糖水平升高的部分原因。为了评估FATP5作为治疗干预的潜在靶点，我们将测试FAT5缺失的动物在饮食和遗传诱导的糖尿病模型中是否显示出减少的脂肪堆积和增加的胰岛素敏感性。我们还将通过产生FATP5转基因小鼠来检验相反的假设是正确的，这可能增加了肝脏LCFA的摄取。