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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.

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Comparison of sn-2 fatty acid substitution (A) and sn-1bond type (B) on total DHA PlsEtn levels in NRel-4 cells. NRel-4 cells were treated with ethanol solvent (N_V), or with test compounds at 20 μM concentration. Compounds C1, C6-10 contain palmityl ether at sn-1 and different fatty acid moieties at sn-2 position; DHA (C1), oleic acid (C7), linoleic acid (C8), linolenic acid (C9), and arachidonic acid (C10), -OH refers to a free hydroxyl group at sn-2 position. Compounds C4 and C5 have acyl linkages at sn-1 and sn-2 positions. Total DHA containing ethanolamine plasmalogens were quantified, and expressed relative to the amount observed in wild-type CHO cells (C_V). Values were an average of three independent experiments. Error bars represent standard deviation.
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Figure 6: Comparison of sn-2 fatty acid substitution (A) and sn-1bond type (B) on total DHA PlsEtn levels in NRel-4 cells. NRel-4 cells were treated with ethanol solvent (N_V), or with test compounds at 20 μM concentration. Compounds C1, C6-10 contain palmityl ether at sn-1 and different fatty acid moieties at sn-2 position; DHA (C1), oleic acid (C7), linoleic acid (C8), linolenic acid (C9), and arachidonic acid (C10), -OH refers to a free hydroxyl group at sn-2 position. Compounds C4 and C5 have acyl linkages at sn-1 and sn-2 positions. Total DHA containing ethanolamine plasmalogens were quantified, and expressed relative to the amount observed in wild-type CHO cells (C_V). Values were an average of three independent experiments. Error bars represent standard deviation.

Mentions: 4. Comparison of compounds C1, C6-10, revealed that whereas DHA containing precursors can partially or fully restore all other sn-2 PlsEtn, non-DHA containing precursors cannot completely restore DHA-PlsEtn (Figure 6A).


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)

Comparison of sn-2 fatty acid substitution (A) and sn-1bond type (B) on total DHA PlsEtn levels in NRel-4 cells. NRel-4 cells were treated with ethanol solvent (N_V), or with test compounds at 20 μM concentration. Compounds C1, C6-10 contain palmityl ether at sn-1 and different fatty acid moieties at sn-2 position; DHA (C1), oleic acid (C7), linoleic acid (C8), linolenic acid (C9), and arachidonic acid (C10), -OH refers to a free hydroxyl group at sn-2 position. Compounds C4 and C5 have acyl linkages at sn-1 and sn-2 positions. Total DHA containing ethanolamine plasmalogens were quantified, and expressed relative to the amount observed in wild-type CHO cells (C_V). Values were an average of three independent experiments. Error bars represent standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Comparison of sn-2 fatty acid substitution (A) and sn-1bond type (B) on total DHA PlsEtn levels in NRel-4 cells. NRel-4 cells were treated with ethanol solvent (N_V), or with test compounds at 20 μM concentration. Compounds C1, C6-10 contain palmityl ether at sn-1 and different fatty acid moieties at sn-2 position; DHA (C1), oleic acid (C7), linoleic acid (C8), linolenic acid (C9), and arachidonic acid (C10), -OH refers to a free hydroxyl group at sn-2 position. Compounds C4 and C5 have acyl linkages at sn-1 and sn-2 positions. Total DHA containing ethanolamine plasmalogens were quantified, and expressed relative to the amount observed in wild-type CHO cells (C_V). Values were an average of three independent experiments. Error bars represent standard deviation.
Mentions: 4. Comparison of compounds C1, C6-10, revealed that whereas DHA containing precursors can partially or fully restore all other sn-2 PlsEtn, non-DHA containing precursors cannot completely restore DHA-PlsEtn (Figure 6A).

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