Abstract
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.
Highlights
Abnormal HDL metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis
We showed that these unsaturated fatty acids accelerate ABCA1 protein turnover through a signaling pathway involving the activation of phospholipase D2 (PLD2) and the phosphorylation of ABCA1 serine residues [27]
We previously demonstrated that the long-chain unsaturated fatty acids palmitoleate, oleate, linoleate, and arachidonate decreased apolipoprotein A-I (apoA-I)-mediated lipid efflux from murine macrophages and ABCA1-transfected Baby hamster kidney (BHK) cells [27] by increasing ABCA1 degradation through a PLD2DAG pathway that increased ABCA1 serine phosphorylation
Summary
Abnormal HDL metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis. Our previous studies showed that the long-chain unsaturated fatty acids palmitoleate, oleate, linoleate, and arachidonate but not the saturated fatty acids palmitate and stearate decrease ABCA1 expression in cells by increasing its protein degradation rate [26]. We showed that these unsaturated fatty acids accelerate ABCA1 protein turnover through a signaling pathway involving the activation of phospholipase D2 (PLD2) and the phosphorylation of ABCA1 serine residues [27].
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