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，具有很大的脂肪酸吸收能力。大量证据表明，除了弥漫性成分外，肠、心脏、脂肪组织和肝脏也表达一种饱和的、特异性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摄取的增加和减少都与2型糖尿病和急性肝衰竭等疾病有关。研究人员发现，几种膜蛋白在培养的哺乳动物细胞中过度表达时，会增加LCFAs的摄取。其中最突出和最具特征的是FAT/CD36和脂肪酸转运蛋白（FATPs，溶质载体家族27）。然而，研究较好的FATPs、FATP1和-4以及CD36在肝脏中的表达水平均不明显。因此，我们已经确定了在肝脏中表达的FATPs，并描述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，FATP5和fat2，作为这一角色的可能候选人。FATP2在肝脏和肾脏中表达，而FATP5的表达是肝脏特异性的。本提案的目的是确定FATP5对肝脏脂肪酸摄取的贡献。为了实现这一目标，我们将确定FATP5在肝脏中的定位和调控，并建立FATP5功能丧失和获得的动物模型。为此，我们产生了FATP5缺失的小鼠，其肝脏脂肪酸摄取减少，肝脏甘油三酯含量降低。我们将使用这个独特的模型系统来探索肝脏LCFA摄取在能量稳态和疾病，特别是2型糖尿病的病因学中的作用。肝脏中过多的TG积累是“代谢综合征”的一个很好的特征，可能在一定程度上导致胰岛素抵抗和葡萄糖水平升高。为了评估FATP5作为治疗干预的潜在靶点，我们将在饮食和遗传诱导的糖尿病模型中测试FAT5缺失的动物是否表现出脂肪积累减少和胰岛素敏感性增加。我们还将通过产生FATP5转基因小鼠来验证相反的假设是正确的，这可能增加了肝脏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.