Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C δ pathway

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 δ (PKCδ)-specific inhibitor rottlerin and PKCδ 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 PKCδ in the ABCA1-destabilizing effects of fatty acids. These data indicate that unsaturated fatty acids destabilize ABCA1 by activating a PKCδ pathway that phosphorylates ABCA1 serines. 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 δ (PKCδ)-specific inhibitor rottlerin and PKCδ 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 PKCδ in the ABCA1-destabilizing effects of fatty acids. These data indicate that unsaturated fatty acids destabilize ABCA1 by activating a PKCδ pathway that phosphorylates ABCA1 serines. Population studies have revealed that HDL is a major cardioprotective factor. 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It is possible that diabetes-associated metabolic factors impair ABCA1 expression or activity and contribute to the higher mortality rate among these patients. 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 (26Wang Y. Oram J.F. Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1..J. Biol. Chem. 2002; 277: 5692-5697Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). Furthermore, we also 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 (27Wang Y. Oram J.F. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway..J. Biol. Chem. 2005; 280: 35896-35903Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). We also found that diacylglycerol (DAG) containing unsaturated but not saturated fatty acyl groups reduced ABCA1 protein levels. In this study, we examined the mechanism by which unsaturated fatty acids destabilize ABCA1 protein. We found that linoleate-induced ABCA1 degradation was associated with increased protein kinase C δ (PKCδ) activity and the phosphorylation of ABCA1 serines. Inhibiting PKCδ with rottlerin or depleting PKCδ with small interfering RNA (siRNA) reduced or abolished the ability of linoleate to promote ABCA1 phosphorylation and degradation. Thus, unsaturated fatty acids activate a PKCδ signaling pathway that phosphorylates ABCA1 serine residues, which destabilizes the protein. LDL and HDL were prepared by sequential ultracentrifugation in the density ranges 1.019–1.063 and 1.125–1.21 g/ml, respectively, and HDL was depleted of apoE and apoB by heparin-agarose chromatography (28Mendez A.J. Oram J.F. Bierman E.L. Protein kinase C as a mediator of high density lipoprotein receptor-dependent efflux of intracellular cholesterol..J. Biol. Chem. 1991; 266: 10104-10111Abstract Full Text PDF PubMed Google Scholar). ApoA-I was purified from HDL and delipidated as described previously (28Mendez A.J. Oram J.F. Bierman E.L. Protein kinase C as a mediator of high density lipoprotein receptor-dependent efflux of intracellular cholesterol..J. Biol. Chem. 1991; 266: 10104-10111Abstract Full Text PDF PubMed Google Scholar). LDL was acetylated by the method of Goldstein et al. (29Goldstein J.L. Ho Y.K. Basu S.K. Brown M.S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition..Proc. Natl. Acad. Sci. USA. 1979; 76: 333-337Crossref PubMed Scopus (1932) Google Scholar). Baby hamster kidney (BHK) cells expressing mifepristone-inducible human ABCA1 were generated as described previously (30Vaughan A.M. Oram J.F. ABCA1 redistributes membrane cholesterol independent of apolipoprotein interactions..J. Lipid Res. 2003; 44: 1373-1380Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Murine RAW 264.7 macrophages and ABCA1-expressing BHK cells were maintained in DMEM (Invitrogen) containing 10% fetal bovine serum or incubated in serum-free DMEM plus 1 mg/ml fatty acid-free BSA (DMEM/BSA). To radiolabel cellular cholesterol, 1 μCi/ml [3H]cholesterol (NEN Life Science Products) was added to the growth medium (BHK cells) or to DMEM/BSA containing 50 μg/ml acetylated LDL (RAW 264.7 macrophages) at 24 h immediately preceding the treatments (26Wang Y. Oram J.F. Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1..J. Biol. Chem. 2002; 277: 5692-5697Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 30Vaughan A.M. Oram J.F. ABCA1 redistributes membrane cholesterol independent of apolipoprotein interactions..J. Lipid Res. 2003; 44: 1373-1380Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Washed cells were then incubated for 6–16 h with medium containing 5 mg/ml BSA in the presence or absence of 125 μM fatty acids (molar ratios to BSA of 0:1.8). Fatty acids were added from a stock solution bound to BSA at a 3.5 molar ratio and were adjusted to ratios by fatty acid-free To ABCA1, was added to the medium for RAW 264.7 and was added to the medium for ABCA1-expressing BHK To cholesterol cells were incubated with DMEM/BSA with or μg/ml for 2 h at and on and the medium was and to The medium was for and the cells were for and [3H]cholesterol by chromatography A.J. Oram J.F. that apolipoprotein A-I in cellular cholesterol..J. Clin. Invest. 1994; PubMed Scopus Google Scholar). cholesterol efflux is as the of [3H]cholesterol into the medium of in the absence of were and from the at in containing To PKCδ or ABCA1, cell were in containing plus and the was incubated at with against PKCδ or ABCA1 The was by protein and in a protein to of of and from RAW 264.7 cells or BHK were by with and by of membrane ABCA1 from RAW 264.7 were from cells by membrane were in and by and ABCA1 was by J.F. Lawn R.M. Garvin M.R. Wade D.P. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages..J. Biol. Chem. 2000; 275: 34508-34511Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar). of membrane protein were added of ABCA1 from ABCA1-expressing BHK cell were in containing plus and of protein were added of PKCδ was by with PKCδ and and were with ABCA1 were by with ABCA1 by ABCA1 serine phosphorylation was PKCδ expressing the of PKCδ which is not to and were into RAW 264.7 macrophages as described in the 2 of mg/ml was with of DMEM/BSA and of and incubated at for was to of DMEM/BSA with 10% fetal bovine serum in of a containing cultured RAW 264.7 macrophages at and and were into RAW 264.7 macrophages Lipid as described in the 1 of μM was with of and 2 of Lipid was in of DMEM/BSA and incubated at for the the Lipid was with the and incubated for an at A of 50 of Lipid was to of DMEM/BSA in of a containing cultured RAW 264.7 macrophages at We previously that the long-chain unsaturated fatty acids palmitoleate, oleate, linoleate, and arachidonate apoA-I-mediated lipid efflux from murine macrophages and ABCA1-transfected BHK cells (27Wang Y. Oram J.F. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway..J. Biol. Chem. 2005; 280: 35896-35903Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar) by increasing ABCA1 degradation through a pathway that increased ABCA1 serine this a we for their to the destabilizing effects of unsaturated fatty acids. of or on apoA-I-mediated cholesterol efflux from ABCA1-expressing BHK cells were incubated for h with or fatty or inhibitor not The inhibitor completely abolished the ability of linoleate to inhibit apoA-I-mediated cholesterol efflux reduce ABCA1 protein levels and increase ABCA1 serine phosphorylation also the effects of linoleate on apoA-I-mediated cholesterol efflux from macrophages not The effects of rottlerin were μM with ABCA1-transfected BHK cells and These that PKCδ mediates the ABCA1-destabilizing effects of fatty acids. To that PKCδ activation is for the ABCA1-destabilizing effects of unsaturated fatty acids, we PKCδ expression with a and the effects of linoleate on ABCA1 activity and levels. We for and as of their higher we murine RAW 264.7 macrophages for these with and levels by and linoleate on protein levels PKCδ abolished the ability of linoleate to inhibit apoA-I-mediated cholesterol efflux to reduce ABCA1 protein levels and to increase the phosphorylation of ABCA1 In or on the ability of linoleate to inhibit ABCA1 cholesterol efflux activity reduce ABCA1 protein or increase ABCA1 serine phosphorylation Thus, PKCδ expression completely the and effects of linoleate, that PKCδ is required for these fatty It was that PKCδ activation is to phosphorylation at F. C. S. J. C. T. kinase is in the of in with protein kinase 2002; PubMed Scopus Google Scholar). To unsaturated fatty acids activate we incubated ABCA1-expressing BHK cells for with linoleate, or and PKCδ In the absence of of the saturated fatty stearate on ABCA1 stability (26Wang Y. Oram J.F. Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1..J. Biol. Chem. 2002; 277: 5692-5697Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, Y. Oram J.F. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway..J. Biol. Chem. 2005; 280: 35896-35903Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). We also showed previously that affect on ABCA1 activity, levels, or which contains an unsaturated fatty acyl the effects of unsaturated fatty acids on these (27Wang Y. Oram J.F. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway..J. Biol. Chem. 2005; 280: 35896-35903Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). of PKCδ revealed that linoleate and markedly increased PKCδ phosphorylation at the saturated fatty stearate and to increase These data indicate that unsaturated fatty acids and a containing an unsaturated fatty acyl PKCδ Metabolic factors that ABCA1 activity have a on cholesterol transport and atherosclerosis. Our previous studies revealed that unsaturated fatty acids impair ABCA1 expression by its degradation rate through a pathway. Here, we evidence that this by increasing the phosphorylation of ABCA1 through a PKCδ signaling pathway. Unsaturated fatty acids reduced ABCA1 protein levels in murine macrophages and ABCA1-transfected BHK of PKCδ with the inhibitor rottlerin or PKCδ levels with reversed the ability of linoleate to increase ABCA1 serine phosphorylation and reduce ABCA1 protein levels. increased the phosphorylation of PKCδ which is associated with These that phosphorylation of ABCA1 through a PKCδ pathway is for the fatty of this We are in the of ABCA1 serine to the residues that are the of Our previous that the fatty pathway activates a protein kinase that ABCA1 for PLD signaling that activate protein and We that containing unsaturated fatty acyl groups mediates the ABCA1-destabilizing effects of (27Wang Y. Oram J.F. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway..J. Biol. Chem. 2005; 280: 35896-35903Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Here, we that a containing an unsaturated fatty acyl activates These that the pathway to in unsaturated fatty acids that function as signaling to activate thus increasing serine phosphorylation and the degradation of studies have shown that PKCδ in RAW 264.7 macrophages A.S. Wang S.M. in RAW 264.7 macrophages..J. 2002; PubMed Scopus Google Scholar). PKCδ to a novel of kinases that and are by S. activation mechanisms and functions for protein kinase J. 2004; PubMed Scopus Google Scholar). It been shown that in murine the receptor the secretion of the activation of PKCδ and PLD of by receptor by protein kinase C and phospholipase D (PLD) in murine 2004; PubMed Scopus Google Scholar), these two Here, that linoleate activate and PKCδ to phosphorylate its downstream Our and previous studies the for the ABCA1-destabilizing effects of fatty acids Unsaturated fatty acids are into the cell by fatty protein and to their of which are into of containing unsaturated acyl These also activate which as a mechanism to and in unsaturated acyl These activate which phosphorylates serine residues in ABCA1 that ABCA1 for PKCδ activate to a of by receptor by protein kinase C and phospholipase D (PLD) in murine 2004; PubMed Scopus Google Scholar). that the fatty of ABCA1 a Fatty acids destabilize ABCA1 a fatty molar ratio in the high (26Wang Y. Oram J.F. Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1..J. Biol. Chem. 2002; 277: 5692-5697Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). unsaturated fatty acids have the the In the presence of LXR which are generated cells cholesterol, the saturated fatty acids palmitate and stearate also ABCA1 are to unsaturated fatty acids by the 1 Y. B. Oram J.F. activation of macrophage unsaturated fatty acids that destabilize Lipid Res. 2004; Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Thus, the activity of the ABCA1 pathway in as is to are to high levels of the fatty acids, and the for this is is consistent with studies of the fatty and metabolic M.S. Goldstein J.L. A pathway that controls the cholesterol of and Natl. Acad. Sci. USA. 1999; PubMed Scopus Google Scholar, of and insulin Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J.J. G. J. Y. J.M. B. Brown M.S. Goldstein J.L. 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