Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo
Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo
Phosphatidylcholine (PC) synthesis by the direct cytidine diphosphate choline (CDP-choline) pathway in rat liver generates predominantly mono- and di-unsaturated molecular species, while polyunsaturated PC species are synthesized largely by the phosphatidylethanolamine-N-methyltransferase (PEMT) pathway. Although altered PC synthesis has been suggested to contribute to development of hepatocarcinoma and nonalcoholic steatohepatitis, analysis of the specificity of hepatic PC metabolism in human patients has been limited by the lack of sensitive and safe methodologies. Here we incorporated a deuterated methyl-d9-labled choline chloride, to quantify biosynthesis fluxes through both of the PC synthetic pathways in vivo in human volunteers and compared these fluxes with those in mice. Rates and molecular specificities of label incorporated into mouse liver and plasma PC were very similar and strongly suggest that label incorporation into human plasma PC can provide a direct measure of hepatic PC synthesis in human subjects. Importantly, we demonstrate for the first time that the PEMT pathway in human liver is selective for polyunsaturated PC species, especially those containing docosahexaenoic acid. Finally, we present a multiple isotopomer distribution analysis approach, based on transfer of deuterated methyl groups to S-adenosylmethionine and subsequent sequential methylations of PE, to quantify absolute flux rates through the PEMT pathway that are applicable to studies of liver dysfunction in clinical studies.
deuterated choline, lipidomics, multiple isotopomer distribution analysis, phosphatidylethanolamine-n-methyltransferase, stable isotope
399-407
Pynn, Christopher J.
fc15bc36-c549-4cc8-9482-5b5459ac12e5
Henderson, Neil G.
2226249e-64f5-49c6-9c10-ed88520a8261
Clark, Howard
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Koster, Grielof
e404c38a-6f48-430a-adf0-5208228cb9e7
Bernhard, Wolfgang
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Postle, Anthony D.
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
November 2010
Pynn, Christopher J.
fc15bc36-c549-4cc8-9482-5b5459ac12e5
Henderson, Neil G.
2226249e-64f5-49c6-9c10-ed88520a8261
Clark, Howard
70550b6d-3bd7-47c6-8c02-4f43f37d5213
Koster, Grielof
e404c38a-6f48-430a-adf0-5208228cb9e7
Bernhard, Wolfgang
a93ed9d7-1f32-42e8-bf9c-c9f0f14ad2a2
Postle, Anthony D.
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Pynn, Christopher J., Henderson, Neil G., Clark, Howard, Koster, Grielof, Bernhard, Wolfgang and Postle, Anthony D.
(2010)
Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo.
Journal of Lipid Research, 52 (2), .
(doi:10.1194/jlr.D011916).
Abstract
Phosphatidylcholine (PC) synthesis by the direct cytidine diphosphate choline (CDP-choline) pathway in rat liver generates predominantly mono- and di-unsaturated molecular species, while polyunsaturated PC species are synthesized largely by the phosphatidylethanolamine-N-methyltransferase (PEMT) pathway. Although altered PC synthesis has been suggested to contribute to development of hepatocarcinoma and nonalcoholic steatohepatitis, analysis of the specificity of hepatic PC metabolism in human patients has been limited by the lack of sensitive and safe methodologies. Here we incorporated a deuterated methyl-d9-labled choline chloride, to quantify biosynthesis fluxes through both of the PC synthetic pathways in vivo in human volunteers and compared these fluxes with those in mice. Rates and molecular specificities of label incorporated into mouse liver and plasma PC were very similar and strongly suggest that label incorporation into human plasma PC can provide a direct measure of hepatic PC synthesis in human subjects. Importantly, we demonstrate for the first time that the PEMT pathway in human liver is selective for polyunsaturated PC species, especially those containing docosahexaenoic acid. Finally, we present a multiple isotopomer distribution analysis approach, based on transfer of deuterated methyl groups to S-adenosylmethionine and subsequent sequential methylations of PE, to quantify absolute flux rates through the PEMT pathway that are applicable to studies of liver dysfunction in clinical studies.
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Published date: November 2010
Keywords:
deuterated choline, lipidomics, multiple isotopomer distribution analysis, phosphatidylethanolamine-n-methyltransferase, stable isotope
Identifiers
Local EPrints ID: 175997
URI: http://eprints.soton.ac.uk/id/eprint/175997
ISSN: 0022-2275
PURE UUID: 50739a2a-45b0-4809-b3d2-87c97002b738
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Date deposited: 02 Mar 2011 11:24
Last modified: 15 Mar 2024 02:32
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Contributors
Author:
Christopher J. Pynn
Author:
Neil G. Henderson
Author:
Howard Clark
Author:
Grielof Koster
Author:
Wolfgang Bernhard
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