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Age-related increase in LDL-cholesterol is associated with enhanced oxidative stress and disturbed sphingolipid metabolism

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Abstract

We investigated alterations in plasma metabolites associated with the age-related increase in circulating concentration of low-density lipoprotein (LDL)-cholesterol. The study included 602 healthy, nondiabetic subjects (aged 30–65 years). Among 393 individuals with LDL-cholesterol within the normal limit at baseline, 56 (14.2 %) developed high fasting LDL-cholesterol levels after 3 years. The 337 subjects that retained normal LDL-cholesterol were matched for age, gender, BMI, and fasting LDL-cholesterol to form the control group (n = 78). At the 3-year follow-up, the high-LDL group showed greater increases in serum total-cholesterol and LDL-cholesterol, plasma oxidized LDL, lipoprotein-associated phospholipase A2 activity, and urinary 8-epi-prostaglandin F2α than the control group after adjusting for baseline levels. The high-LDL group also showed significant decreases in sphingomyelin (SM) (d18:0/16:1) and phosphatidylcholine (PC) (18:0/20:4), which were associated with an increases on LDL-cholesterol, and significant increases in palmitic amide and lactosylceramide. Mean changes in the levels of SM (d18:0/16:1), C17 sphinganine, PC (18:0/20:4), and eight lysoPCs containing C16:1, C16:0, C17:0, C18:1, C18:0, C20:4, C20:3, and C22:6 were statistically different between control and high-LDL groups. Overall, the change in ox-LDL positively correlated with changes in LDL-cholesterol, Lp-PLA2 activity, palmitic amide, oleamide, lysoPCs, and C17 sphinganine, and negatively correlated with changes in SM (d18:0/16:1) (r = −0.501, P < 0.001). An age-related increase in LDL-cholesterol is associated with enhanced oxidative stress and disturbed sphingolipid metabolism.

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Acknowledgments

Sample collection and experiments were performed by S. J., M. K., H. J. R., J. S. C., S-H. L., and J. H. L. Data were analyzed by S. J., M. K, and J. H. L. J. H. L. provided the research funding and S. J., M. K., and J. H. L. wrote the manuscript. All of the authors read, commented on, and contributed to the submitted manuscript. No potential conflicts of interest relevant to this article were reported. The authors thank the research volunteers who participated in the studies described in this article and the technical assistants of Yonsei Center for Research Facilities, Yonsei University, for data generation of LC–MS (LTQ Orbitrap (micro-LC)). This research was supported by the Bio and Medical Technology Development Program (NRF-2006-2005306 and NRF-2012M3A9C4048762) and Mid-career Researcher Program (NRF-2010-0015017) of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea.

Conflict of interest

None of the authors have a conflict of interest relevant to this work.

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all participants for being included in the study.

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Authors and Affiliations

  1. National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, College of Human Ecology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, Korea

    Saem Jung, Minjoo Kim, Hyo Jeong Ryu & Jong Ho Lee

  2. Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea

    Saem Jung, Minjoo Kim & Jong Ho Lee

  3. Yonsei University Research Institute of Science for Aging, Yonsei University, Seoul, Korea

    Jey Sook Chae & Jong Ho Lee

  4. Department of Family Practice, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea

    Sang-Hyun Lee

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  1. Saem Jung
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  2. Minjoo Kim
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  3. Hyo Jeong Ryu
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Correspondence to Jong Ho Lee.

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Jung, S., Kim, M., Ryu, H.J. et al. Age-related increase in LDL-cholesterol is associated with enhanced oxidative stress and disturbed sphingolipid metabolism. Metabolomics 11, 40–49 (2015). https://doi.org/10.1007/s11306-014-0669-3

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  • DOI: https://doi.org/10.1007/s11306-014-0669-3

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