Grant Abstract: Functions of vitamin E and the tocopherol transfer protein

Grant Number: 1R01DK125115-01A1
PI Name: Manor
Project Title: Functions of vitamin E and the tocopherol transfer protein

Abstract: 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. PUBLIC HEALTH RELEVANCE: Vitamin E is an essential nutrient that is required for the integrity of cells, especially those of the nervous system. TTP is a protein expressed in the liver and the brain that regulates the levels and distribution of vitamin E in the body. We propose to study new, previously-undescribed functions of vitamin E and TTP and how they offer protection from disease. Upon the successful completion of the proposed studies, we will have resolved fundamental enigmas regarding the biology of vitamin E and TTP. These findings stand to influence a paradigm shift, likely to have profound impact on our understanding and treatments of relevant disease states.

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