TY - JOUR
T1 - N-acyl-O-phosphocholineserines
T2 - Structures of a novel class of lipids that are biomarkers for Niemann-Pick C1 disease
AU - Sidhu, Rohini
AU - Mondjinou, Yawo
AU - Qian, Mingxing
AU - Song, Haowei
AU - Kumar, Arun Babu
AU - Hong, Xinying
AU - Hsu, Fong Fu
AU - Dietzen, Dennis J.
AU - Yanjanin, Nicole M.
AU - Porter, Forbes D.
AU - Berry-Kravis, Elizabeth
AU - Vite, Charles H.
AU - Gelb, Michael H.
AU - Schaffer, Jean E.
AU - Ory, Daniel S.
AU - Jiang, Xuntian
N1 - Funding Information:
This work was supported by National Institutes of Health Clinical and Translational Science Award UL1 TR000448 (X.J.) and Grants R01 NS081985 (D.S.O. and J.E.S.), P41-GM103422 (F-F.H), and 2R01DK067859 (M.H.G.); grants from the University of Pennsylvania Orphan Disease Center (X.J.), Dana's Angels Research Trust (D.S.O. and N.M.Y.), and Ara Parseghian Medical Research Foundation (D.S.O. and N.M.Y.); support from Accelerated Research for NPC Disease (D.S.O.), Hope for Hayley and Samantha's Search for the Cure Funds (E.B.K.), and Referral Center for Animal Models of Human Genetic Disease (National Institutes of Health Grant P40 OD010939; C.H.V.). This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.) and a Bench to Bedside Award from the Office of Rare Diseases (F.D.P. and D.S.O.). This work was performed in the Metabolomics Facility at Washington University (National Institutes of Health Grant P30 DK020579). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This work was supported by National Institutes of Health Clinical and Translational Science Award UL1 TR000448 (X.J.) and Grants R01 NS081985 (D.S.O. and J.E.S.), P41-GM103422 (F-F.H), and 2R01DK067859 (M.H.G.); grants from the University of Pennsylvania Orphan Disease Center (X.J.), Dana’s Angels Research Trust (D.S.O. and N.M.Y.), and Ara Parseghian Medical Research Foundation (D.S.O. and N.M.Y.); support from Accelerated Research for NPC Disease (D.S.O.), Hope for Hayley and Samantha’s Search for the Cure Funds (E.B.K.), and Referral Center for Animal Models of Human Genetic Disease (National Institutes of Health Grant P40 OD010939; C.H.V.). This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.) and a Bench to Bedside Award from the Office of Rare Diseases (F.D.P. and D.S.O.). This work was performed in the Metabolomics Facility at Washington University (National Institutes of Health Grant P30 DK020579). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Manuscript received 24 May 2019 and in revised form 13 June 2019. Published, JLR Papers in Press, June 14, 2019 DOI https://doi.org/10.1194/jlr.RA119000157
Publisher Copyright:
Copyright © 2019 Sidhu et al.
PY - 2019
Y1 - 2019
N2 - Niemann-Pick disease type C1 (NPC1) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, there is an urgency to improve diagnostics and monitor therapeutic efficacy with biomarkers. In this study, we sought to define the structure of an unknown lipid biomarker for NPC1 with [M + H]+ ion at m/z 509.3351, previously designated as lysoSM-509. The structure of N-palmitoyl-O-phosphocholineserine (PPCS) was proposed for the lipid biomarker based on the results from mass spectrometric analyses and chemical derivatizations. As no commercial standard is available, authentic PPCS was chemically synthesized, and the structure was confirmed by comparison of endogenous and synthetic compounds as well as their derivatives using liquid chromatographytandem mass spectrometry (LC-MS/MS). PPCS is the most abundant species among N-acyl-O-phosphocholineserines (APCS), a class of lipids that have not been previously detected in biological samples. Further analysis demonstrated that all APCS species with acyl groups ranging from C14 to C24 were elevated in NPC1 plasma. PPCS is also elevated in both central and peripheral tissues of the NPC1 cat model. Identification of APCS structures provide an opportunity for broader exploration of the roles of these novel lipids in NPC1 disease pathology and diagnosis.-Sidhu, R., Y. Mondjinou, M. Qian, H. Song, A. B. Kumar, X. Hong, F-F. Hsu, D. J. Dietzen, N. M. Yanjanin, F. D. Porter, E. Berry- Kravis, C. H. Vite, M. H. Gelb, J. E. Schaffer, D. S. Ory, and X. Jiang. N-acyl-O-phosphocholineserines: structures of a novel class of lipids that are biomarkers for Niemann-Pick C1 disease. J. Lipid Res. 2019. 60: 1410-1424.
AB - Niemann-Pick disease type C1 (NPC1) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, there is an urgency to improve diagnostics and monitor therapeutic efficacy with biomarkers. In this study, we sought to define the structure of an unknown lipid biomarker for NPC1 with [M + H]+ ion at m/z 509.3351, previously designated as lysoSM-509. The structure of N-palmitoyl-O-phosphocholineserine (PPCS) was proposed for the lipid biomarker based on the results from mass spectrometric analyses and chemical derivatizations. As no commercial standard is available, authentic PPCS was chemically synthesized, and the structure was confirmed by comparison of endogenous and synthetic compounds as well as their derivatives using liquid chromatographytandem mass spectrometry (LC-MS/MS). PPCS is the most abundant species among N-acyl-O-phosphocholineserines (APCS), a class of lipids that have not been previously detected in biological samples. Further analysis demonstrated that all APCS species with acyl groups ranging from C14 to C24 were elevated in NPC1 plasma. PPCS is also elevated in both central and peripheral tissues of the NPC1 cat model. Identification of APCS structures provide an opportunity for broader exploration of the roles of these novel lipids in NPC1 disease pathology and diagnosis.-Sidhu, R., Y. Mondjinou, M. Qian, H. Song, A. B. Kumar, X. Hong, F-F. Hsu, D. J. Dietzen, N. M. Yanjanin, F. D. Porter, E. Berry- Kravis, C. H. Vite, M. H. Gelb, J. E. Schaffer, D. S. Ory, and X. Jiang. N-acyl-O-phosphocholineserines: structures of a novel class of lipids that are biomarkers for Niemann-Pick C1 disease. J. Lipid Res. 2019. 60: 1410-1424.
KW - LysoSM-509
KW - Mass spectrometry
KW - Niemann-Pick disease type C
KW - Structural identification
UR - http://www.scopus.com/inward/record.url?scp=85071055471&partnerID=8YFLogxK
U2 - 10.1194/jlr.RA119000157
DO - 10.1194/jlr.RA119000157
M3 - Article
C2 - 31201291
AN - SCOPUS:85071055471
SN - 0022-2275
VL - 60
SP - 1410
EP - 1424
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 8
ER -