Advisor - Dr. Earl Harrison, Dean's Distinguished Professor, Department of Human Sciences
My dissertation research seeks to understand the biochemical mechanisms required to maintain whole body vitamin A (VA) homeostasis. Nearly all tissues in the body require VA. VA plays an important role in vision, normal growth and development, reproduction, and immunity. In a well-nourished person, most of the VA consumed is stored in the liver and these stores are an indicator of overall VA status. The liver is responsible for maintaining the flux of VA throughout the body and has the ability to respond to dynamic changes in dietary intake. When the nutrient is abundant in the diet, the liver stores esterified forms of VA. In contrast, when dietary VA is limited, the liver is able to release the free form of VA into the blood in order to maintain homeostasis. The disruption of this very fine-tuned regulation can have devastating consequences on the individual’s health and result in diseases. When blood levels of VA are below a certain threshold, it results in vitamin A deficiency (VAD) and its associated disorders. VAD, affecting 100 million people worldwide, is the leading cause of preventable blindness in children and contributes to high prevalence of maternal and child mortality in developing countries. Many genes involved in VA storage in the liver have been described. However, the enzyme involved in the hepatic uptake of VA is not established. After reviewing the literature, I hypothesize that ES-10 is the enzyme physiologically responsible for the uptake of VA in the liver. To establish this, my dissertation proposes to use cell culture approaches and animal models. Thus, these studies will extend molecular understanding of a process that is essential for the body to accumulate liver stores of VA taken up from the diet. Also, there are individual differences in the efficiency of hepatic uptake of VA that significantly influences the storage of this essential nutrient. It is likely that genetic variants of ES-10 contribute to the efficiency of VA storage and explain why individuals are more or less efficient in storing VA, which may impact an individual’s susceptibility to VAD. There is also recent work suggesting an association between blood levels of VA and its plasma binding protein RBP4 and the incidence of obesity, insulin resistance, liver disease, and cardiovascular disease. Thus, the studies proposed are significant because they will investigate a process that is fundamentally important for controlling blood VA levels and will enhance our understanding of the development of metabolic diseases.