Molecular Physiology of Liver Fatty Acid Transporters

描述（由申请人提供）：肝脏脂质积累与肝脏胰岛素抵抗的发展有关。特别是，在肥胖个体中，长期升高的血清游离脂肪酸（FFA）和高胰岛素水平导致肝脏对FFA的摄取增加，脂质合成增加，导致肝脏脂肪变性。在这里，我们假设肝脏FATPs是多功能蛋白质，既促进蛋白质介导的脂肪酸摄取/激活，也促进胆汁激活，将肝脏脂肪酸和固醇代谢联系起来。我们认为，抑制肝脏FATPs可能会改变器官间和细胞内脂质通量，从而影响肝脏脂肪变性、胰岛素敏感性、全身葡萄糖稳态以及胆石症等胆汁相关疾病。我们将通过确定肝脏FATPs的转运和酶活性的相互依赖性，以及确定抑制肝脏FATPs可以改善肝骨化病和其他肝胆疾病以及胰岛素抵抗的机制，在体外和体内证明这种多功能作用。为了解决体内抑制肝脏FATPs的生物学和治疗意义，我们开发并实施了腺相关病毒（AAV）介导的shRNA表达系统、基因敲除方法和基于反义寡核苷酸（ASOs）的方案，这些方案将用于描述抑制肝脏FATPs可以改善肥胖相关的肝胆疾病和胰岛素敏感性的范围和机制。最终，我们的研究将证明肝脏FATPs是否可以作为治疗肥胖相关肝胆疾病和糖尿病的新靶点。

DESCRIPTION (provided by applicant): Accumulation of hepatic lipids has been linked to the development of hepatic insulin resistance. Particularly, in obese individuals chronically elevated serum free fatty acids (FFA) and high insulin levels lead to increased FFA uptake by the liver and increased synthesis of lipids resulting in hepatic steatosis. Here we postulate that hepatic FATPs are multifunctional proteins facilitating both protein-mediated fatty acid uptake/activation as well as bile activation, linking hepatic fatty acid and sterol metabolism. We propose that inhibiting liver FATPs may alter inter-organ and intracellular lipid fluxes and therefore influence hepatic steatosis, insulin sensitivity, whole body glucose homeostasis, as well as bile related diseases such as cholelithiasis. We will demonstrate this multifunctional role in vitro and in vivo by determining the interdependence of transport and enzymatic activities of hepatic FATPs and by determining the mechanism by which inhibition of hepatic FATPs can improve hepatosteatosis and other hepatobiliary disorders as well as insulin resistance. To address the biological and therapeutical implications of suppression of hepatic FATPs in vivo, we have developed and implemented adeno-associated virus (AAV) mediated shRNA expression systems, genetic knockout approaches, and anti- sense oligo nucleotide (ASOs) based regiments which will be used to delineate the extend and mechanisms by which inhibition of hepatic FATPs can improve obesity related hepatobiliary disease and insulin sensitivity. Ultimately, our studies will demonstrate whether hepatic FATPs could represent novel targets for the treatment of obesity associated hepatobiliary diseases as well as diabetes. PUBLIC HEALTH RELEVANCE: Understanding the molecular link between obesity and chronic disease, diabetes in particular, is of crucial importance for public health. Buildup of lipids in the liver is a critical step in the development of obesity- associated diabetes. Thus we will attempt to improve diabetic symptoms by reducing the uptake and accumulation of lipids in this important organ.