4.6 Article

Formation of cholesterol ozonolysis products in vitro and in vivo through a myeloperoxidase-dependent pathway

Journal

JOURNAL OF LIPID RESEARCH
Volume 52, Issue 1, Pages 87-97

Publisher

ELSEVIER
DOI: 10.1194/jlr.M006775

Keywords

secosterol; neutrophils; myeloperoxidase; inflammation

Funding

  1. Japan's Ministry of Education, Science, Culture, and Sport [18509001, 21300280, 19700592, 21680052]
  2. Japan's Ministry of Health, Labor, and Welfare [19-19, 21-1-2]
  3. Japan Health Science Foundation for Health Sciences Focusing on Drug Innovation [KHC1023]

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3 beta-Hydroxy-5-oxo-5,6-secocholestan-6-al (secosterol-A) and its aldolization product 3 beta-hydroxy-5 beta hydroxy-B-norcholestane-6 beta-carboxaldehyde (secosterol-B) were recently detected in human atherosclerotic tissues and brain specimens, and they may play pivotal roles in the pathogenesis of atherosclerosis and neurodegenerative diseases. However, as their origin remains unidentified, we examined the formation mechanism, the stability, and the fate of secosterols in vitro and in vivo. About 40% of secosterol-A remained unchanged after 3 h incubation in the FBS-free medium, whereas 20% and 40% were converted to its aldehyde-oxidation product, 3 beta-hydroxy-5-oxo-secocholestan-6-oic acid, and secosterol-B, respectively. In the presence of FBS, almost all secosterol-A was converted immediately to these compounds. Secosterol-B in the medium, with and without FBS, was relatively stable, but similar to 30% was converted to its aldehyde-oxidation product, 3 beta-hydroxy-5 beta-hydroxy-B-norcholestane-6-oic acid (secoB-COOH). When neutrophillike differentiated human leukemia HL-60 (nHL-60) cells activated with PMA were cultured in the FBS-free medium containing cholesterol, significantly increased levels of secosterol-A and its aldehyde-oxidation product, but not secosterol-B, were formed. This secosterol-A formation was decreased in the culture of PMA-activated nHL-60 cells containing several reactive oxygen species (ROS) inhibitors and scavengers or in the culture of PMA-activated neutrophils isolated from myeloperoxidase (MPO)-deficient mice. Our results demonstrate that secoterol-A is formed by an ozone-like oxidant generated with PMA-activated neutrophils through the MPO-dependent mechanism.-Tomono, S., N. Miyoshi, H. Shiokawa, T. Iwabuchi, Y. Aratani, T. Higashi, H. Nukaya, and H. Ohshima. Formation of cholesterol ozonolysis products in vitro and in vivo through a myeloperoxidase-dependent pathway. J. Lipid Res. 2011. 52: 87-97.

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