Molecular Physiology of Liver Fatty Acid Transporters

描述（由申请人提供）：肝脏是协调大部分代谢的中心器官，具有很大的脂肪酸摄取能力。大量的证据表明，除了扩散成分外，肠、心脏、脂肪组织和肝脏还表达可饱和的特异性长链脂肪酸转运系统。确定假定的肝脏脂肪酸转运蛋白是相当重要的，因为增加和减少的肝脏LCFA摄取都与2型糖尿病和急性肝衰竭等疾病有关。研究人员已经发现了几种膜蛋白，当在培养的哺乳动物细胞中过表达时，它们会增加LCFA的摄取。其中最突出和最具特征的是FAT/CD 36和脂肪酸转运蛋白（FATP，溶质载体家族27）。然而，无论是更好地研究的FATP，FATP 1和-4，也没有CD 36在肝脏中以可感知的水平表达。因此，我们鉴定了在肝脏中表达的FATP，并表征了它们对蛋白质介导的LCFA摄取和一般能量稳态的贡献。我们已经确定了两个FATP家族成员，FATP 5和-2，作为这个角色的可能候选人。FATP 2在肝脏和肾脏中表达，而FATP 5表达是肝脏特异性的。本提案的目的是确定FATP 5对肝脏脂肪酸摄取的贡献。为了实现这一目标，我们将确定FATP 5在肝脏中的定位和调节，并建立FATP 5功能丧失和获得的动物模型。为此，我们已经产生了FATP 5缺失小鼠，其显示出减少的肝脂肪酸摄取和减少的肝甘油三酯含量。我们将使用这个独特的模型系统来探索肝脏LCFA摄取对能量稳态的作用和疾病的病因学，特别是2型糖尿病。过度的肝脏TG积累是“代谢综合征”的一个充分描述的特征，并且可能部分地导致胰岛素抵抗和葡萄糖水平升高。为了评估FATP 5作为治疗干预的潜在靶点，我们将测试FAT 5缺失动物在饮食和遗传诱导的糖尿病模型中是否显示脂质积累减少和胰岛素敏感性增加。我们还将通过产生FATP 5转基因小鼠来检验匡威的假设，这些小鼠可能增加了肝脏LCFA的摄取。

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.