Phosphatidylinositol acts through mitogen-activated protein kinase to stimulate hepatic apolipoprotein A-I secretion.
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 mumol/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 kinase (MAPK) inhibitors. Whereas the p38MAPK inhibitor SB203580 has no effect on PI-induced apo A-I secretion, the MAPK kinase 1/2 inhibitor U0126 and the c-Jun-N-terminal kinase/stress-activated protein kinase inhibitor SP600125 block PI-induced apo A-I secretion. PI also increased extracellular-regulated protein kinase 1 and 2 phosphorylation in HepG2 cells in a time-dependent manner. PI does not appear to stimulate apo A-I gene transcription, as cellular apo A-I messenger RNA levels remained unchanged over the 24-hour incubation. However, PI significantly decreases apo A-I binding and degradation in HepG2 cells. Collectively, the data suggest that PI acts through MAPK pathways to increase plasma apo A-I levels by protecting it from reuptake and degradation.
Hopewell
Shawn
S
Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
Pandey
Nihar R
NR
Misquith
Ayesha
A
Twomey
Erin
E
Sparks
Daniel L
DL
D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010716:Phosphatidylinositols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism
D016632:Apolipoprotein A-I; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases