Phosphatidylinositol acts through mitogen-activated protein kinase to stimulate hepatic apolipoprotein A-I secretion》.pdfVIP

Available online at Metabolism Clinical and Experimental 57 (2008) 1677 – 1684 Phosphatidylinositol acts through mitogen-activated protein kinase to stimulate hepatic apolipoprotein A-I secretion a a,b b a a,b,⁎ Shawn Hopewell , Nihar R. Pandey , Ayesha Misquith , Erin Twomey , Daniel L. Sparks aLipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7 bLiponex, Inc, 1390 Prince of Wales Dr 205, Ottawa, Ontario, Canada K1Y 4W7 Received 14 April 2008; accepted 3 July 2008 Abstract Phosphatidylinositol (PI) has been shown to stimulate reverse cholesterol transport in animal models and to increase plasma apolipoprotein (apo) A-I levels and high-density lipoprotein cholesterol in human subjects. The objective of this study was to determine the molecular mechanism through which PI stimulates apo A-I secretion in hepatic cells. PI (12 μmol/L) significantly stimulates apo A-I secretion from HepG2 cells over 24 hours. The stimulation in apo A-I secretion is completely blocked by phospholipase C inhibitors (D609 and U73122) and the Ras inhibitor sulindac sulfide. Apolipoprotein A-I secretion is augmented with a protein kinase C agonist (dioctanoyl glycerol) and inhibited by a protein kinase C inhibitor (dioleoyl ethylene glycol). The PI-induced apo A-I secretion is unaffected by PI-3- kinase inhibitors but is sensitive to mitogen-activated protein