Effects of phosphatidylinositol on ApoA-I metabolism: Implications in HDL metabolism

Title: Effects of phosphatidylinositol on ApoA-I metabolism: Implications in HDL metabolism
Authors: Hopewell, Shawn
Date: 2008
Abstract: Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the developed world. Attempts to prevent CHD using LDL lowering medications have been only partly successful and new approaches are under investigation. Significant efforts are being made to develop therapeutics that raise plasma HDL levels to aid in the prevention of CHD. HDL levels are believed to be inversely associated with the risk of developing CHD. Naturally occurring phospholipids such as phosphatidylinositol (PI), have been shown to increase plasma apoA-I levels and HDL levels in animal models and human subjects; but the mechanism remains to be elucidated. Since in humans, HDL is primarily synthesized in the liver, the objective of the present study was to evaluate the underlying molecular mechanism of PI-induced apoA-I and HDL secretion from liver cells. We show that PI doubles apoA-I/HDL secretion at 24h in a model hepatocyte, HepG2, cell culture system. PI-induced apoA-I secretion is unaffected by PI-3-kinase inhibitors but is sensitive to various MAP kinase inhibitors. While the p38MAPK inhibitor SB203580 has no effect on PI-induced apoA-I secretion, the MEK1/2 inhibitor U0126 blocks PI-induced apoA-I secretion. Inhibition of the JNK MAPK pathway by SP600125 also blocks PI mediated apoA-I secretion. Real-time PCR shows no changes in cellular apoA-I mRNA and suggests that PI is not impacting the transcription of the apoA-I gene. However, the degradation of apoA-I is decreased in PI treated HepG2 cells. Collectively, the data from these investigations suggest that PI acts through mitogen and stress-activated protein kinase pathways to increase plasma apoA-I levels by decreasing the degradation of apoA-I.
URL: http://hdl.handle.net/10393/27987
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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