Betaine and Choline Improve Lipid Homeostasis in Obesity by Participation in Mitochondrial Oxidative Demethylation

Sivanesan, Sugashan; Taylor, Adrian; Zhang, Junzeng; Bakovic, Marica

doi:10.3389/fnut.2018.00061

Cited by 43 publications

(33 citation statements)

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“…Based on our extensive work on CTL1 and Cho transport (3)(4)(5)(6)(7)(8)15) and known similarities between Cho and Etn transports in various conditions (12-14) we postulated that CTL1 could be that long-searched for Etn/Cho transporter and the last missing link between CDP-Cho and CDP-Etn pathways for phospholipids synthesis. We conducted an extensive number of kinetic, metabolic, and genetic experiments to solidify this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…The role of plasma membrane CTL1 is assigned to Cho transport for PC synthesis, but the exact function of the mitochondrial CTL1 is still not clear. In the liver and kidney, mitochondrial CTL1 transports Cho for oxidation to betaine, the major methyl donor in the one-carbon cycle (6). In other tissues however, the mitochondrial CTL1 probably maintains the intracellular pools of Cho and as a H + -antiporter and modulates the electrochemical/proton gradient in the mitochondria (7,8).…”

Section: Introductionmentioning

confidence: 99%

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The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Taylor

Grapentine

Ichhpuniani

et al. 2020

Preprint

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We examined a novel function of mammalian Choline-Transporter-Like proteins CTL1/SLC44A1 and CTL2/SLC44A2 in ethanolamine transport. We established two distinct ethanolamine transport systems of a high affinity (K1 = 55.6 - 66.5 μM), mediated by CTL1, and of a low affinity (K2 = 275 - 299 μM), mediated by CTL2. Both types of transport are Na+-independent and mediated in a pH dependent manner, as expected for ethanolamine/H+ antiporters. Primary human fibroblasts with separate frameshift mutations (M1= SLC44A1ΔAsp517 and M2= SLC44A1ΔSer126) are devoid of CTL1 ethanolamine transport but maintain unaffected CTL2 transport. The lack of CTL1 or CTL2 reduced the ethanolamine transport, the flux by the CDP-ethanolamine Kennedy pathway and PE synthesis. Overexpression of CTL1 in SLC44A1ΔSer126 (M2) cells improved the ethanolamine transport and PE synthesis. The SLC44A1ΔSer126 cells are reliant on CTL2 function and CTL2 siRNA almost completely abolished ethanolamine transport in the whole cells and mitochondria. Overexpression of CTL1 and CTL2 cDNAs increased ethanolamine transport in control and SLC44A1ΔSer126 cells. CTL1 and CTL2 facilitated mitochondrial ethanolamine uptake, but the transport mediated by CTL1 is predominant in the whole cells and mitochondria. These data firmly established that CTL1 and CTL2 are the first identified ethanolamine transporters in the whole cells and mitochondria, with intrinsic roles in de novo PE synthesis by the CDP-Etn Kennedy pathway and compartmentation of intracellular ethanolamine.SignificanceThe lack of Choline Transporter Like 1 (SLC44A1/CTL1) is the primary cause of a new neurodegenerative disorder with elements of childhood-onset parkinsonism and mitochondrial dysfunction. SLC44A2/CTL2 encodes the human neutrophil antigen 3, causes autoimmune hearing loss and Meniere’s disease, and has been recently identified as the main risk factor for thrombosis-the major cause of death in Covid-19 patients. Our investigation provides insights into the novel functions of CTL1 and CTL2 as intrinsic ethanolamine transporters. CTL1 and CTL2 are high and low affinity transporters, with direct roles in the membrane phospholipid synthesis. The work contributes to new knowledge for CTL1 and CTL2 independent transport functions and the optimization of prevention and treatment strategies in those various diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Taylor

Grapentine

Ichhpuniani

et al. 2020

Preprint

Self Cite

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“…The plasma membrane CTL1 is firmly assigned to Cho transport for PC synthesis ( 15 ), yet the exact function of the mitochondrial CTL1 is still not clear. In the liver and kidney mitochondria, Cho is specifically oxidized to betaine, the major methyl donor in the one-carbon cycle ( 6 ). Since it is broadly expressed, it is proposed that the mitochondrial CTL1 could maintain the intracellular pools of Cho and as + H-antiporter could regulate the electrochemical/proton gradient in the mitochondria ( 5 , 15 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…CTL3, -4, and -5 are poorly characterized members of the family, and their transport functions are not clearly established ( 3 , 4 ). Based on our extensive work on CTL1 and Cho transport ( 3 , 4 , 5 , 6 , 7 , 8 , 15 ) and known similarities between Cho and Etn transports in various conditions ( 12 , 13 , 14 ) we postulated that CTL1 could be that long-searched-for Etn/Cho transporter and the last missing link between CDP-Cho and CDP-Etn pathways for phospholipids synthesis. We conducted an extensive number of kinetic, metabolic, and genetic experiments to solidify this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…PC could also produce PS by a similar exchange mechanism, with free Cho being released. The metabolically released Cho and Etn need to be transported in and out of the cytosol and mitochondria or reincorporated into the Kennedy pathway ( 3 , 4 , 5 , 6 ). That mammalian Etn and Cho transport may occur through a similar transport system was implicated from early kinetic studies in bovine endothelial cells, human retinoblastoma cells, and glial cells ( 12 , 13 , 14 ).…”

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confidence: 99%

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Choline transporter-like proteins 1 and 2 are newly identified plasma membrane and mitochondrial ethanolamine transporters

Taylor

Grapentine

Ichhpuniani

et al. 2021

Journal of Biological Chemistry

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The membrane phospholipids phosphatidylcholine and phosphatidylethanolamine (PE) are synthesized de novo by the CDP-choline and CDP-ethanolamine (Kennedy) pathway, in which the extracellular substrates choline and ethanolamine are transported into the cell, phosphorylated, and coupled with diacylglycerol to form the final phospholipid product. Although multiple transport systems have been established for choline, ethanolamine transport is poorly characterized and there is no single protein assigned a transport function for ethanolamine. The solute carriers 44A (SLC44A) known as choline transporter-like proteins-1 and -2 (CTL1 and CTL2) are choline transporter at the plasma membrane and mitochondria. We report a novel function of CTL1 and CTL2 in ethanolamine transport. Using the lack or the gain of gene function in combination with specific antibodies and transport inhibitors we established two distinct ethanolamine transport systems of a high affinity, mediated by CTL1, and of a low affinity, mediated by CTL2. Both transporters are Na + -independent ethanolamine/H + antiporters. Primary human fibroblasts with separate frameshift mutations in the CTL1 gene (M1= SLC44A1 ΔAsp517 and M2= SLC44A1 ΔSer126 ) are devoid of CTL1 ethanolamine transport but maintain unaffected CTL2 transport. The lack of CTL1 in M2 cells reduced the ethanolamine transport, the flux through the CDP-ethanolamine Kennedy pathway, and PE synthesis. In contrast, overexpression of CTL1 in M2 cells improved ethanolamine transport and PE synthesis. These data firmly establish that CTL1 and CTL2 are the first identified ethanolamine transporters in whole cells and mitochondria, with intrinsic roles in de novo PE synthesis by the Kennedy pathway and intracellular redistribution of ethanolamine.

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Anticancer Natural Alkaloids as Drug Bank Targeting Biomolecules

Bhadra¹

2021

Handbook of Smart Materials, Technologies, and Devices

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Betaine and Choline Improve Lipid Homeostasis in Obesity by Participation in Mitochondrial Oxidative Demethylation

Cited by 43 publications

References 35 publications

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Choline transporter-like proteins 1 and 2 are newly identified plasma membrane and mitochondrial ethanolamine transporters

Anticancer Natural Alkaloids as Drug Bank Targeting Biomolecules

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