Regulation of the expression of key genes involved in HDL metabolism by unsaturated fatty acids.
The cardioprotective effects of HDL have been largely attributed to their role in the reverse cholesterol transport pathway, whose efficiency is affected by many proteins involved in the formation and remodelling of HDL. The aim of the present study was to determine the effects, and possible mechanisms of action, of unsaturated fatty acids on the expression of genes involved in HDL metabolism in HepG2 cells. The mRNA concentration of target genes was assessed by real-time PCR. Protein concentrations were determined by Western blot or immunoassays. PPAR and liver X receptor (LXR) activities were assessed in transfection experiments. Compared with the SFA palmitic acid (PA), the PUFA arachidonic acid (AA), EPA and DHA significantly decreased apoA-I, ATP-binding cassette A1 (ABCA1), lecithin-cholesterol acyltransferase (LCAT) and phospholipid transfer protein mRNA levels. EPA and DHA significantly lowered the protein concentration of apoA-I and LCAT in the media, as well as the cellular ABCA1 protein content. In addition, DHA repressed the apoA-I promoter activity. AA lowered only the protein concentration of LCAT in the media. The activity of PPAR was increased by DHA, while the activity of LXR was lowered by both DHA and AA, relative to PA. The regulation of these transcription factors by PUFA may explain some of the PUFA effects on gene expression. The observed n-3 PUFA-mediated changes in gene expression are predicted to reduce the rate of HDL particle formation and maturation.
Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA              02111, USA.
Yu-Lin
YL
Kuang
K Eric
KE
Paulson
Alice H
AH
Lichtenstein
Stefania
S
Lamon-Fava
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D008076:Cholesterol, HDL / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism / Q000494:pharmacology*; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D000071518:Liver X Receptors; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology*; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D004041:Dietary Fats; D000071518:Liver X Receptors; D056913:Mediator Complex Subunit 1; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D019308:Palmitic Acid; D015118:Eicosapentaenoic Acid; D007862:Phosphatidylcholine-Sterol O-Acyltransferase