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Choline Transport and Metabolism in Genetically Deficient and Chronic Disease States

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Title: Choline Transport and Metabolism in Genetically Deficient and Chronic Disease States
Author: Cigana Schenkel, Laila
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Bakovic, Marica
Abstract: Choline is required for the biosynthesis of phosphatidylcholine (PC) by the CDP-choline Kennedy pathway and of betaine. Choline also plays a role in lipid metabolism and hepatic and muscle function. The availability of intracellular choline is regulated by the choline transporter CTL1/SLC44A1 at the plasma membrane. This thesis aims to elucidate the effect of metabolic altered states, such as lipid overload, choline deficiency and CDP:phopshoethanolamine cytidylyltransferase (Pcyt2) genetic modified models, on the choline transport and metabolism. First, we investigated the effect of high fatty acid supply in C2C12 muscle cells. Palmitic acid (PAM) reduced total and plasma membrane CTL1/SLC44A1 protein by activating lysosomal degradation, and limited the choline uptake while increasing diacylglycerol (DAG) and triacylglycerol (TAG) synthesis. Oleic acid (OLA) maintained total and plasma membrane CTL1/SLC44A1, increasing PC and TAG synthesis more than PAM, which offers a protection mechanism from the excess of intracellular DAG and autophagy. We next characterized the choline metabolic defect in fibroblast cells isolated from a Postural Tachycardia Syndrome (POTS) patient, who had low plasma choline. In the POTS fibroblasts, the CTL1/SLC44A1 expression and choline uptake were decreased. PC synthesis and the phospholipid pool were reduced these cells compared to control. Triacylglycerol formation increased 50% in POTS, which is a feature of choline deficiency. The characteristics of the POTS fibroblasts represent a model of choline transport dysfunction. The role of choline in protecting against lipid accumulation and metabolic disease development was elucidated by choline supplementation of Pcyt2+/- mice. In Pcyt2+/- mice the CDP-ethanolamine pathway is downregulated and the TAG formation increased, resulting in adult-onset obesity and liver steatosis. Choline supplementation reverses the Pcyt2+/- phenotype by facilitating the metabolic flux through the CDP-choline pathway, reducing TAG synthesis and increasing expression of genes involved in TAG and DAG degradation. The cross-regulation between CDP-choline and CDP-ethanolamine pathways was also demonstrated in Pcyt2 siRNA knock-down human fibroblasts (KD5), where the rate of choline uptake and PC synthesis were higher. Altogether, this thesis established the metabolic links between CDP-choline and CDP-ethanolamine pathways and provided a mechanism of how choline could be an important modifier of lipid metabolism under various conditions.
Date: 2014-08
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