Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway.
Abnormal HDL metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis. ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are increased in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein. We previously reported that unsaturated fatty acids destabilize ABCA1 in murine macrophages and ABCA1-transfected baby hamster kidney cells by increasing its serine phosphorylation through a phospholipase D (PLD) pathway. Here, we examined the cellular pathway downstream of PLD that mediates the ABCA1-destabilizing effects of unsaturated fatty acids. The protein kinase C delta (PKCdelta)-specific inhibitor rottlerin and PKCdelta small interfering RNA completely abolished the ability of unsaturated fatty acids to inhibit lipid transport activity, to reduce protein levels, and to increase serine phosphorylation of ABCA1, implicating a role for PKCdelta in the ABCA1-destabilizing effects of fatty acids. These data indicate that unsaturated fatty acids destabilize ABCA1 by activating a PKCdelta pathway that phosphorylates ABCA1 serines.
Wang
Yutong
Y
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Oram
John F
JF
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004075:Diglycerides; D005231:Fatty Acids, Unsaturated; D034741:RNA, Small Interfering; D051745:Protein Kinase C-delta