Lipid-bound apolipoproteins in tyrosyl radical-oxidized HDL stabilize ABCA1 like lipid-free apolipoprotein A-I

In the current study we determined that tyrHDL requires functional ABCA1 for this enhanced activity. Like lipid-free apolipoprotein A-I (apoA-I), tyrHDL increases total and cell surface ABCA1, inhibits calpain-dependent and -independent proteolysis of ABCA1, and can be bound by cell surface ABCA1 in human skin fibroblasts. Additionally, tyrHDL apoproteins are susceptible to digestion by enteropeptidase like lipid-free apoA-I, but unlike lipid-bound apoA-I on HDL, which is resistant to proteolysis.These results provide the first evidence that lipid-bound apolipoproteins on the surface of spherical HDL particles can behave like lipid-free apoA-I to increase ABCA1 protein levels and activity.High density lipoprotein cholesterol (HDL-C) levels in human plasma correlate generally with protection against coronary heart disease, an effect believed to be due to multiple protective actions of HDL including stimulating the removal of excess cholesterol from cells and reducing inflammation in the artery wall [1]. The initial formation of HDL particles requires the membrane lipid transporter ATP-binding cassette transporter A1 (ABCA1) to mediate delivery of cellular lipids to HDL apolipoproteins. This reduces excess cholesterol stores in cells including arterial wall macrophages [2]. In addition to receiving cellular lipids, lipid-free apolipoprotein A-I (apoA-I) binds to and inhibits the degradation of ABCA1, further enhancing the formation of HDL particles [3,4]. Lipidated apoA-I on the surface of discoidal or spherical HDL particles, however, has a reduced affinity for ABCA1 and does not inhibit ABCA1 degradation [3,5]. These findings suggest structural motifs present in lipid-free but not lipid-bound apoA-I participate in ABCA1 binding and enhancement of ABCA1 cell surface stability.In addition to increasing ABCA1 expression transcriptionally, therapies that increase ABCA1 cell surface stability represent a potential means to increase HDL production. We previously showed th