Abstract
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.
Highlights
Cholesterol is an essential lipid molecule having many important biological functions, such as regulation of the general physicochemical properties of the biomembrane, formation of its microdomains with sphingomyelin to accommodate various signal-related molecules, direct modification of a key signal protein hedgehog for development, and biosynthesis of steroid hormones and bile acids
We demonstrate that the protein kinase C (PKC) signaling pathway plays an essential role in the apolipoprotein A-I (apoA-I)-induced stabilization and phosphorylation of ATP-binding cassette transporter A1 (ABCA1)
ApoA-I increased ABCA1 in a time-dependent manner (Fig. 1A). It became apparent within 30 min and was evident even after substantial cholesterol removal by 24-h incubation
Summary
Cholesterol is an essential lipid molecule having many important biological functions, such as regulation of the general physicochemical properties of the biomembrane, formation of its microdomains with sphingomyelin to accommodate various signal-related molecules, direct modification of a key signal protein hedgehog for development, and biosynthesis of steroid hormones and bile acids. 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. We demonstrate that the protein kinase C (PKC) signaling pathway plays an essential role in the apoA-I-induced stabilization and phosphorylation of ABCA1.
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