Apolipoprotein A-I activates protein kinase C alpha signaling to phosphorylate and stabilize ATP binding cassette transporter A1 for the high density lipoprotein assembly.
ATP-binding cassette transporter A1 (ABCA1) plays an essential role in the helical apolipoprotein-mediated assembly of high density lipoprotein, and the apolipoporteins stabilize ABCA1 against calpain-mediated degradation during the reaction ((2002) J. Biol. Chem. 277, 22426-22429). Protein kinase C (PKC) inhibitors suppressed both ABCA1 stabilization and cellular lipid release mediated by apolipoprotein A-I (apoA-I) but not ABCA1 increase by calpain inhibitors. The increase of ABCA1 and the cellular lipid release by apoA-I were both suppressed by a phosphatidylcholine phospholipase C (PC-PLC) inhibitor but not by the inhibitors of phosphatidylinositol-PLC and phosphatidylinositol 3-kinase. A protein phosphatase inhibitor further enhanced the ABCA1 increase by apoA-I. Biochemical and microscopic evidence indicated that apoA-I activated PKC alpha, and phosphorylation of ABCA1 was directly demonstrated by apoA-I via PKC. Finally, digestion of sphingomyelin increased ABCA1, and a PC-PLC inhibitor suppressed it. We conclude that apoA-I activates PKC alpha by PC-PLC-mediated generation of diacylglycerol initiated by the removal of cellular sphingomyelin ((2002) J. Biol. Chem. 277, 44709-44714), and subsequently phosphorylates and stabilizes ABCA1.
Yamauchi
Yoshio
Y
Department of Biochemistry, Cell Biology, and Metabolism, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Hayashi
Michi
M
Abe-Dohmae
Sumiko
S
Yokoyama
Shinji
S
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000502:physiology*; D001053:Apolipoproteins / Q000378:metabolism; D015153:Blotting, Western; D002154:Calpain / Q000037:antagonists & inhibitors; D002460:Cell Line; D004075:Diglycerides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013109:Sphingomyelins / Q000378:metabolism; D013997:Time Factors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D004075:Diglycerides; D004791:Enzyme Inhibitors; D008075:Lipoproteins, HDL; D008164:Luminescent Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D013109:Sphingomyelins; D049452:Green Fluorescent Proteins; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D002154:Calpain