Functions of vitamin E and the tocopherol transfer protein

α-生育酚（维生素E）是人体必需的营养素和主要的脂溶性抗氧化剂。维生素E最重要的健康促进作用被认为是保护中枢神经系统（CNS）免受活性物质或自由基引起的膜，蛋白质和核酸损伤。体内维生素E的水平和分布受肝脏α生育酚转移蛋白（TTP）调节，后者调节维生素从肝脏分泌到循环脂蛋白，进而分泌到所有组织。因此，TTPA基因突变是维生素E缺乏性共济失调的唯一已知原因（AVID; OMIM 277460）。多年来，我们的研究已经确定了α-生育酚和TTP的关键功能和作用机制，并且我们已经取得了重要的发现，详细说明了TTP如何在肝脏和小脑的细胞中转运维生素。所提出的研究将集中在三个至关重要的领域：1）我们将破译TTP促进α-生育酚从内吞区室运输到质膜的分子机制。2)我们将研究维生素E的新的抗氧化剂独立活动的分子机制和生理后果，以及它们对维生素E缺乏小鼠模型神经健康的后果。3)我们将破译维生素E阻止非酒精性脂肪性肝病病理进展为严重的不可逆肝病（非酒精性脂肪性肝炎）的机制。我们的研究结果将为维生素E在健康和疾病中的作用提供重要的新见解。

Alpha-tocopherol (vitamin E) is an essential nutrient and the major fat-soluble antioxidant in humans. The most critical health-promoting action of vitamin E is thought to be anchored in protecting the central nervous system (CNS) from damage to membranes, proteins and nucleic acids induced by reactive species or free radicals. The levels and distribution of vitamin E in the body are regulated by hepatic alpha tocopherol transfer protein (TTP), which regulates secretion of the vitamin from the liver to circulating lipoproteins, and in turn to all tissues. Accordingly, mutations in the TTPA gene are the only known cause for ataxia with vitamin E deficiency (AVED; OMIM 277460). Our studies over the years have identified critical functions and mechanisms of action of a-tocopherol and TTP and we have made important discoveries that detail how TTP transports the vitamin across cells in the liver and the cerebellum. The proposed research will focus on three areas of critical importance: 1) we will decipher the molecular mechanisms underlying TTP-facilitation of trafficking of a- tocopherol from the endocytic compartment to the plasma membrane. 2) We will examine the molecular mechanisms and physiological consequences of novel, antioxidant independent activities of vitamin E, and their consequences on neurological health in a mouse model of vitamin E deficiency. 3) We will decipher the mechanisms by which vitamin E prevents the pathological progression of non alcoholic fatty liver disease to severe, irreversible liver disease (non alcoholic steatohepatitis). The results from our studies will provide important new insight into the role of vitamin E in health and disease.