THE ROLE OF KIAA1363 IN HEPATIC RETINYL ESTER MOBILIZATION

Vitamin A is a micronutrient that is essential for life. Mammals store large quantities of vitamin A in the liver. This liver store of vitamin A is utilized under times of insufficient nutritional intake, to ensure a constant supply of the body. Interestingly, under pathological conditions, when liver disease progresses to a more advanced stage, the vitamin A of the liver is lost. This event represents a turning point of liver disease to a non-reversible disease state. The mobilization of vitamin A requires the action of specific enzymes. Despite the important role of vitamin A-mobilizing enzymes in liver physiology, the protein responsible for this process is currently unknown. In preliminary experiments, we identified an enzyme to exhibit this specific feature of mobilizing stored vitamin A. We have investigated this enzymatic function under experimental conditions but also in living cells. Interestingly, this enzyme is expressed in specific liver cells, that are specialized to store vitamin A. Thus, we hypothesize that this enzyme may acts as vitamin A mobilizing enzyme in the liver, thereby controlling vitamin A levels of the body. In this project, we will employ a genetic mouse model lacking this enzyme. We will use this mouse model to investigate the functional role of this enzyme in vitamin A metabolism of the liver. Further, we will also employ a vitamin A free feeding regime to specifically investigate the essential role of this enzyme in vitamin A metabolism under conditions vitamin A undersupply. Finally, we will also examine the specific role of this enzyme in the progression of liver disease. We speculate that mice lacking this enzyme will show an attenuated loss of vitamin A stores in certain liver cells. This attenuation of vitamin A depletion of the liver may slow down the progression of liver disease. Thus, the pharmacological inhibition of vitamin A mobilization in the liver may represent a therapeutic option for the intervention of liver disease.

Vitamin A is an essential micronutrient that is stored primarily in the liver in mammals. This vitamin A store is used to maintain a constant supply of the body during periods of insufficient dietary intake. Interestingly, this vitamin A store is lost under pathological conditions of liver disease. This occurs at the time of advanced liver disease and represents a turning point, as it marks the transition to an irreversible disease. The mobilization of vitamin A is accomplished by specific proteins. Despite the important role of these vitamin A-mobilizing proteins, their role in maintaining a constant vitamin A supply under different nutritional conditions and in the process of liver disease is poorly understood. In this project, we investigated the role of two different proteins in maintaining the body's vitamin A supply using genetic mouse models. Firstly, we were able to show that a specific protein in adipose tissue plays a crucial role during food deprivation. If this protein is specifically lacking in adipose tissue, a constant supply of vitamin A of the body cannot be maintained during food deprivation. This leads, among other things, to a lower concentration of vitamin A in the circulation and to insufficient supply to various tissues. Secondly, the absence of another protein, which is found in the liver, among other tissues, led to an increase in vitamin A levels in specific lipid storage cells of the liver. However, this change in the distribution of vitamin A levels in the liver did not generally affect the body's vitamin A supply; however, the vitamin A levels in the eye were increased in these animals. This suggests that this protein also plays a specific role in the eye in vitamin A supply. Interestingly and against expectations, the absence of the vitamin A mobilizing enzyme had no effect on the disease progression in a fibrosis mouse model. In this project, we were able to show that vitamin A mobilizing proteins of specific tissues play an important function in maintaining vitamin A homeostasis of the body. The extent to which an impairment of this constant vitamin A supply has a physiological significance for the function of various tissues requires future studies.