Apolipoprotein A-II regulates HDL stability and affects hepatic lipase association and activity

Lipid transfer inhibitor protein (LTIP) is a physiologic regulator of cholesteryl ester transfer protein (CETP) function. We previously reported that LTIP activity is localized to LDL, consistent with its greater inhibitory activity on this lipoprotein. With a recently described immunoassay for LTIP, we investigated whether LTIP mass is similarly distributed. Plasma fractionated by gel filtration chromatography revealed two LTIP protein peaks, one coeluting with LDL, and another of ?470 kDa. The 470 kDa LTIP complex had a density of 1.134 g/ml, indicating ?50% lipid content, and contained apolipoprotein A-I. By mass spectrometry, partially purified 470 kDa LTIP also contains apolipoproteins C-II, D, E, J, and paraoxonase 1. Unlike LDL-associated LTIP, the 470 kDa LTIP complex does not inhibit CETP activity. In normolipidemic subjects, ?25% of LTIP is in the LDLassociated, active form. In hypercholesterolemia, this increases to 50%, suggesting that lipoprotein composition may influence the status of LTIP activity. Incubation (37°C) of normolipidemic plasma increased active, LDL-associated LTIP up to 3-fold at the expense of the inactive pool. Paraoxon inhibited this shift by 50%. Overall, these studies show that LTIP activity is controlled by its reversible incorporation into an inactive complex. This may provide for short-term fine-tuning of lipoprotein remodeling mediated by CETP.-He, Y., D. J. Greene, M. Kinter, and R. E. Morton. In plasma, cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester (CE) from LDL and HDL to VLDL in return for triglyceride (TG) (1, 2). This remodeling of lipoprotein composition alters the metabolism of lipoproteins and ultimately influences both the quality and quantity of lipoproteins in plasma (3-5). Physiologically, CETP may be regulated by at least two proteins. Apolipoprotein C-I, which resides primarily on HDL, has been reported to inhibit CETP in vitro, and studies with transgenic animals have demonstrated its ability to suppress CETP activity in vivo (6, 7). Its mode of action is via modification of the surface charge of HDL, resulting in weakened CETP-HDL interactions and thus suppression of lipid transfer events with HDL (8). A second regulatory protein is lipid transfer inhibitor protein (LTIP), also known as apolipoprotein F (9). Although the mechanism of inhibition of CETP by LTIP has not been firmly established, it also appears to function by disrupting the interaction of CETP with its substrate (10). However, the effects of LTIP on lipid transfer events are quite distinct from that of apolipoprotein C-I. Unlike apolipoprotein C-I, LTIP activity is associated with LDL (11). The addition of exogenous LTIP to native plasma reduces the participation of LDL in lipid transfer events but leads to a dose-dependent increase in the efflux of CE from HDL to VLDL. This enhanced CETP activity on HDL results in HDL particles that are markedly better substrates for lecithin:cholesterol acyltransferase (11). We have proposed that this increa...

“…Finally, hepatic lipase activity is regulated by its binding to HDL. Tighter binding of hepatic lipase to apolipoprotein A-II containing HDL particles renders it inactive (29).…”

Section: Discussionmentioning

confidence: 99%

Control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex

He¹,

Greene

Kinter

et al. 2008

“…The physiological role of apoA-II remains unclear. Experimental data indicate that apoA-II is likely to maintain the plasma HDL pool and enhance HDL stability by inhibiting hepatic lipase activity and CETP-mediated dissociation of lipid-poor apoA-I (17,18). It has been also shown that the rate of apoA-II production determines the distribution of apoA-I between HDL A-I and HDL A-I/A-II (19).…”

mentioning

confidence: 99%

Phospholipids mediated conversion of HDLs generates specific apoA-II pre-β mobility particles

Wróblewska

Kortas-Stempak

Szutowicz

et al. 2009

Apolipoproteins (apo)A-I and A-II are major proteins of human HDL. The cycling of apoA-I between lipidpoor and lipid-rich forms of HDL plays a key role in the transport of cholesterol by these particles. ApoA-II resides only in part of HDL particles, and little is known about its role in HDL metabolism. Our study investigates the redistribution of apoA-II after HDL remodelling induced by exogenous phospholipids (PL). During incubation with egg yolk lecithin (EYL) liposomes, human HDL became PL-enriched and free cholesterol (FC)-depleted, and lost small amounts of apoA-I and apoA-II. The loss of FC and apolipoproteins correlated with the rise of PL content in HDL. Agarose gel electrophoresis demonstrated the appearance of new pre-b mobility fractions containing apoA-I and apoA-II in liposomes and HDL mixtures. Two-dimensional nondenaturing 2-27% PAGE has shown that the pre-b mobility fraction that appeared at initial liposome-PL/HDL-PL ratio 5:1 consisted of two distinct heterogeneous subpopulations of particles containing either apoA-I or apoA-II. Our study provides evidence that during HDL conversion mediated by PL apoA-II dissociated from HDL particles yielding apoA-II-specific pre-b mobility particles. This observation supports the hypothesis that apoA-II in plasma, like apoA-I, may cycle between lipid-poor and lipid-rich forms of HDL.-Wróblewska, M., B. KortasStempak, A. Szutowicz, and T. Badzio. Phospholipids mediated conversion of HDLs generates specific apoA-II pre-b mobility particles. J. Lipid Res. 2009. 50: 667-675.

“…It has previously been shown by several groups that the interaction between apoA-I and PON1 is important for stabilizing enzyme activity and improving specific activity (12,(25)(26)(27). ApoA-II, through its ability to stabilize HDL structure (8), may complement the stabilizing influence of apoA-I, if not present at excess levels. In contrast, apoA-II alone has a negative impact on PON1 activity (25).…”

Section: Discussionmentioning

confidence: 99%

“…Animal models have indicated that overexpression of apoA-II is detrimental for atherosclerosis (6,7), although the interpretation of such models is open to question. ApoA-II exhibits greater hydrophobicity than apoA-I, binds more tightly to lipids, and appears to stabilize the HDL complex (8). Its hydrophobic nature may be a factor in the influence of apoA-II on HDL-associated enzyme activity, by modulating interactions of enzymes with the lipoprotein.…”

mentioning

confidence: 99%

HDL subfraction distribution of paraoxonase-1 and its relevance to enzyme activity and resistance to oxidative stress

Moren

Deakin

Liu

et al. 2008