|Kuang, Yu-Lin -|
|Paulson, K. Eric -|
|Lichtenstein, Alice H. -|
|Lamon-Fava, Stefania -|
Submitted to: British Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 14, 2011
Publication Date: January 1, 2012
Citation: Kuang, Y., Paulson, K., Lichtenstein, A., Lamon-Fava, S. 2012. Regulation of the expression of key genes involved in HDL metabolism by unsaturated fatty acids. British Journal of Nutrition. DOI: 10.1017/S0007114511006854. Interpretive Summary: Population studies have shown that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to the risk of cardiovascular disease. It is thought that the cardioprotective effect of HDL is due to its ability to pick up cholesterol from the arterial wall and bring it to the liver, where it can be excreted in the bile. In addition, a high dietary intake of fish is associated with a reduced risk of cardiovascular disease. The aim of this study was to assess the role of different types of fatty acids in regulating the proteins that are involved in the synthesis and maturation of HDL in plasma. Our experiments were carried out in the hepatoma cell line HepG2, which synthesizes all these proteins. We found that the omega-3 fatty acids EPA and DHA, which are found in fatty fish, reduced the synthesis of apolipoprotein A-I (apo A-I), the major protein component of HDL, and of ABCA1, the cell membrane transporter involved in the cell cholesterol efflux to HDL. Other proteins were also affected. These results indicate that omega-3 fatty acids may lower the production and formation of HDL. However, it should be pointed out that the cardioprotective effects of HDL are not simply determined by plasma HDL-C concentrations but also depend on the function of HDL, and therefore the effects of these fatty acids on HDL functionality need to be investigated.
Technical Abstract: The aim of this 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 receptors (LXR) activities were assessed in transfection experiments. Compared to the saturated fatty acid palmitic acid (PA), the PUFA arachidonic acid (AA), EPA and DHA, significantly decreased apo A-I, ATP-binding cassette (ABC) A1, lecithin-cholesterol acyltransferase (LCAT), and phospholipid transfer protein mRNA levels. EPA and DHA significantly lowered the protein concentration of apo A-I and LCAT in the media, as well as the cellular ABCA1 protein content. In addition, DHA repressed the apo A-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.