Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study

Lipids in Health and Disease

Research

Khine K Su-Myat¹  Hong Ma¹  Pearson WK Ahiahonu¹  Dayan B Goodenowe¹  Paul L Wood¹  Dushmanthi Jayasinghe¹  Rishikesh Mankidy¹  Shawn A Ritchie¹  Mohamed A Khan¹ 

[1] Phenomenome Discoveries Inc. and Phreedom Pharma, 204-407 Downey Road, S7N 4L8, Saskatoon, SK, Canada;

关键词: Cholesterol;    Free Cholesterol;    Membrane Cholesterol;    Structure Activity Relationship Study;    Refsum Disease;   

DOI  :  10.1186/1476-511X-9-62

 received in 2010-04-27, accepted in 2010-06-14,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundDisrupted cholesterol regulation leading to increased circulating and membrane cholesterol levels is implicated in many age-related chronic diseases such as cardiovascular disease (CVD), Alzheimer's disease (AD), and cancer. In vitro and ex vivo cellular plasmalogen deficiency models have been shown to exhibit impaired intra- and extra-cellular processing of cholesterol. Furthermore, depleted brain plasmalogens have been implicated in AD and serum plasmalogen deficiencies have been linked to AD, CVD, and cancer.ResultsUsing plasmalogen deficient (NRel-4) and plasmalogen sufficient (HEK293) cells we investigated the effect of species-dependent plasmalogen restoration/augmentation on membrane cholesterol processing. The results of these studies indicate that the esterification of cholesterol is dependent upon the amount of polyunsaturated fatty acid (PUFA)-containing ethanolamine plasmalogen (PlsEtn) present in the membrane. We further elucidate that the concentration-dependent increase in esterified cholesterol observed with PUFA-PlsEtn was due to a concentration-dependent increase in sterol-O-acyltransferase-1 (SOAT1) levels, an observation not reproduced by 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition.ConclusionThe present study describes a novel mechanism of cholesterol regulation that is consistent with clinical and epidemiological studies of cholesterol, aging and disease. Specifically, the present study describes how selective membrane PUFA-PlsEtn enhancement can be achieved using 1-alkyl-2-PUFA glycerols and through this action reduce levels of total and free cholesterol in cells.

【 授权许可】

Unknown   
© Mankidy et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.