Molecular Physiology of Liver Fatty Acid Transporters

描述(由申请人提供)：肝脏脂质的积聚与肝脏胰岛素抵抗的发展有关。尤其是在肥胖者中，长期升高的血清游离脂肪酸(FFA)和高胰岛素水平会导致肝脏对FFA摄取增加和脂质合成增加，从而导致肝脏脂肪变性。我们推测，肝脏FATP是一种多功能蛋白质，既促进蛋白质介导的脂肪酸摄取/激活，又促进胆汁活化，连接肝脏脂肪酸和甾醇代谢。我们认为，抑制肝脏脂肪转运蛋白可能会改变器官间和细胞内的脂质通量，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汁相关疾病，如胆石症。我们将在体外和体内通过确定肝脏FATPs转运和酶活性的相互依赖以及通过确定抑制肝脏FATPs改善肝骨病和其他肝胆疾病以及胰岛素抵抗的机制来证明这一多功能作用。为了解决体内抑制肝脏FATPs的生物学和治疗意义，我们开发和实施了腺相关病毒(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FATP可以改善肥胖相关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，肝脏脂肪相关蛋白是否可以作为治疗肥胖相关肝胆疾病和糖尿病的新靶点。 公共卫生相关性：了解肥胖和慢性疾病，特别是糖尿病之间的分子联系，对公共卫生至关重要。肝脏中脂质的积聚是肥胖相关糖尿病发展的关键一步。因此，我们将试图通过减少这一重要器官中脂质的摄取和积累来改善糖尿病症状。

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.