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SLC44A1 Transport of Choline and Ethanolamine in Disease

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Title: SLC44A1 Transport of Choline and Ethanolamine in Disease
Author: Taylor, Adrian
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Bakovic, Marica
Abstract: Choline and ethanolamine are important molecules required for the de novo synthesis of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) via the Kennedy pathway. Additionally, these two molecules are vital for maintaining both muscular and neurological function. The goal of this thesis was to gain insight into PC and PE metabolism with the use of unique metabolic disturbances ranging from obesity and genetic mutations in neurodegenerative disease. Firstly, the protective effects of choline supplementation on muscular function were investigated within the Pcyt2+/- mouse model. In Pcyt2+/- mice, substrate flow through the CDP-ethanolamine branch of the Kennedy pathway was diminished resulting in triacylglycerol (TAG) accumulation and obesity. Supplemental choline improved muscle function by altering the expression of genes devoted to reducing TAG synthesis and restoring energy homeostasis. With this new insight about the role of choline in regulating metabolism, the cellular uptake mechanism of choline was then analyzed. Skin fibroblasts from two patients with homozygous mutations in the SLC44A1 gene suffering from Neurodegeneration with Brain Iron Accumulation (NBIA) were utilized. In these fibroblasts, SLC44A1 expression and choline uptake were drastically diminished. Moreover, PC levels were unaffected while PE levels were diminished relative to control, an indication of perturbed phospholipid homeostasis. Within this model of choline transport dysfunction, choline supplementation moderately improved phospholipid homeostasis. In the literature, there are data which suggest that the same transporter might facilitate choline and ethanolamine uptake. This prompted us to examine the role of SLC44A1 in ethanolamine transport. SLC44A1 was overexpressed in cells to understand its influence in ethanolamine uptake. Moreover, cells with defects in SLC44A1 mediated transport were utilized to characterize ethanolamine uptake kinetics. Additionally, choline and ethanolamine appeared to compete for uptake while antibody inhibition of SLC44A1 diminished PC and PE levels. Lastly, it was determined that ethanolamine uptake occurs in a pH dependent manner. SLC44A1 mediated uptake has previously been characterized as being pH dependent, which was further evidence implicating SLC44A1 in ethanolamine transport. This thesis solidifies the metabolic relationships between the CDP-choline and CDP-ethanolamine pathways and the connection between choline and ethanolamine in regulating lipid homeostasis.
Date: 2019-04
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