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

Mankidy R, Ahiahonu PW, Ma H, Jayasinghe D, Ritchie SA, Khan MA, Su-Myat KK, Wood PL, Goodenowe DB - Lipids Health Dis (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Phenomenome Discoveries Inc, and Phreedom Pharma, 204-407 Downey Road, Saskatoon, SK S7N 4L8, Canada.

ABSTRACT

Background: Disrupted 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.

Results: Using 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.

Conclusion: The 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.

Show MeSH

Related in: MedlinePlus

Side chain-specific restoration of PlsEtn in NRel-4 cells. Effect of C1, C2, C3, C6-10 treatment of NRel-4 (N_V) cells on sn-1 specific PlsEtn pools.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2902472&req=5

Figure 4: Side chain-specific restoration of PlsEtn in NRel-4 cells. Effect of C1, C2, C3, C6-10 treatment of NRel-4 (N_V) cells on sn-1 specific PlsEtn pools.

Mentions: 1. Maintaining the free alcohol at sn-3 and DHA at sn-2, PlsEtn precursors C1-3 with differing long chain ether substitutions at sn-1 revealed that these precursor compounds either partially or fully restored all ethanolamine plasmalogens with the same sn-1 alkyl ether but had no effect on PlsEtn with different sn-1 compositions (Figure 4). For example, treatment with a palmityl PlsEtn precursor (C1) restored the downstream pool of 16:0 ethanolamine plasmalogens with no effect on the 18:0 and 18:1 PlsEtn pools. Such side chain-specific restoration indicates that no rearrangement of the sn-1 moiety (O-alkyl linkage) occurs, while the sn-2 moiety is able to undergo deacylation and subsequent reacylation with other fatty acid residues.


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

Mankidy R, Ahiahonu PW, Ma H, Jayasinghe D, Ritchie SA, Khan MA, Su-Myat KK, Wood PL, Goodenowe DB - Lipids Health Dis (2010)

Side chain-specific restoration of PlsEtn in NRel-4 cells. Effect of C1, C2, C3, C6-10 treatment of NRel-4 (N_V) cells on sn-1 specific PlsEtn pools.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902472&req=5

Figure 4: Side chain-specific restoration of PlsEtn in NRel-4 cells. Effect of C1, C2, C3, C6-10 treatment of NRel-4 (N_V) cells on sn-1 specific PlsEtn pools.
Mentions: 1. Maintaining the free alcohol at sn-3 and DHA at sn-2, PlsEtn precursors C1-3 with differing long chain ether substitutions at sn-1 revealed that these precursor compounds either partially or fully restored all ethanolamine plasmalogens with the same sn-1 alkyl ether but had no effect on PlsEtn with different sn-1 compositions (Figure 4). For example, treatment with a palmityl PlsEtn precursor (C1) restored the downstream pool of 16:0 ethanolamine plasmalogens with no effect on the 18:0 and 18:1 PlsEtn pools. Such side chain-specific restoration indicates that no rearrangement of the sn-1 moiety (O-alkyl linkage) occurs, while the sn-2 moiety is able to undergo deacylation and subsequent reacylation with other fatty acid residues.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Phenomenome Discoveries Inc, and Phreedom Pharma, 204-407 Downey Road, Saskatoon, SK S7N 4L8, Canada.

ABSTRACT

Background: Disrupted 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.

Results: Using 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.

Conclusion: The 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.

Show MeSH
Related in: MedlinePlus