Article pubs.acs.org/biochemistry
Neo High-Density Lipoprotein Produced by the Streptococcal Serum Opacity Factor Activity against Human High-Density Lipoproteins Is Hepatically Removed via Dual Mechanisms Perla J. Rodriguez,†,‡ Baiba K. Gillard,† Rachel Barosh,† Antonio M. Gotto, Jr.,† Corina Rosales,† and Henry J. Pownall*,† †
Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, United States
‡
S Supporting Information *
ABSTRACT: Injection of streptococcal serum opacity factor (SOF) into mice reduces the plasma cholesterol level by ∼40%. In vitro, SOF converts highdensity lipoproteins (HDLs) into multiple products, including a small HDL, neo HDL. In vitro, neo HDL accounts for ∼60% of the protein mass of the SOF reaction products; in vivo, the accumulated mass of neo HDL is 50% [3H]CE was obtained. HDL was floated and unreacted FC removed by multiple incubations with LDL (5 mL of a 5.8 mg/mL solution, 3 h at 37 °C), after which the density was adjusted to 1.063 g/ mL and the LDL floated and removed. This was repeated with additional LDL until thin layer chromatography (TLC) showed >98% of the radiolabel as CE. FC to CE conversion was followed by TLC on silica plates developed in an 80:20 (v/v) hexane/ethyl acetate solvent. CE- and FC-positive spots were β-counted, and the percent radiochemical purity was calculated. The HDL was concentrated by flotation (d = 1.21 g/mL), giving [3H]CE-labeled HDL. Size exclusion chromatography (SEC) showed the radiolabel eluting only as HDL. [3H]CElabeled HDL was then used for the SOF reaction as described below to isolate [3H]CE-labeled neo HDL. Isolation of Neo HDL-[3H]CE. A polyhistidine-tagged, truncated form of sof2 encoding amino acids 38−843 was cloned, expressed in Escherichia coli, and purified by metal affinity chromatography as described previously.9,23 HDL[3H]CE (100 mg) was incubated with SOF (17 μg) in 50 mL of TBS overnight at 37 °C, after which the sample was centrifuged at 40000 rpm in a Beckman Ti 50.2 rotor for 18 h. The CERM (∼10 mL) was removed from the top of the tube by pipet, and the infranatant was removed from the bottom in 2 mL fractions and analyzed by SEC over two Superose HR6 columns in tandem. The fractions richest in neo HDL were pooled and adjusted to a d of 1.28 g/mL by the addition of KBr and floated at 40000 rpm (Beckman Ti 50.2 rotor) for 72 h. Fractions (2 mL) were removed from the bottom and analyzed by SEC; those containing neo HDL and devoid of other lipids and proteins were pooled for experiments. B
DOI: 10.1021/acs.biochem.6b00946 Biochemistry XXXX, XXX, XXX−XXX
Article
Biochemistry
min at 4 °C to isolate plasma; 100 μL aliquots were β-counted. The mice were then perfused with saline, and the heart, lungs, spleen, kidneys, liver, and testes were collected and frozen at −20 °C until they could be processed. Tissues were weighed, and small portions of each were homogenized, lyophilized, the lipid extracted with a 3:2 (v/v) hexane/2-propanol solvent, which was transferred to scintillation vials, evaporated, and βcounted. Plasma was analyzed for triglycerides, total cholesterol, and phospholipids with kits (Wako). Statistical Analysis. Where appropriate, values are expressed as means ± the standard error. Data were compared by analysis of variance and a Student’s t test for pairwise comparison between neo HDL serum assays with and without inhibitors. p values of LDL ≫ HDL ∼ TLP (Table 1). This order was the same in the presence of LPDS, which accelerated the transfer of neo HDL-[3H]CE to the larger HDL. The decrease in transfer half-times by LPDS was the least profound
Figure 3. Neo HDL-[3H]CE cell uptake does not occur primarily by SR-B1 selective uptake. (A) Immunoblot for SR-B1 expression in CHO-derived cell lines (2 μg loaded): CHO-ldlA7 cells, CHOldlA7[SR-B1] cells, CHO-K1 cells, and Huh7 hepatocytes (20 μg loaded). (B) Measure of CE uptake per milligram of cell protein for each cell line over 3 h fit to a linear curve. (C) Immunoblot for SR-B1 expression in Huh7 cells (15 μg loaded): p1399CMV-hSR-B1-V5HIS-transfected cells, p116.2AAV-EGFP-cB-transfected cells, and nontransfected Huh7 hepatocytes from left to right, respectively. (D) Relative band intensity quantification for SR-B1 protein expression and GAPDH. (E) Measure of CE uptake as HDL or neo HDL per milligram of cell protein for each cell over a 3 h uptake. Error bars show the standard error. ***p < 0.001; *p < 0.05.
component of serum that interacts with neo HDL to give a neo HDL remnant, termed simply as remnant hereafter. Incubation of neo HDL with HDL for ≥30 min led to contraction of neo HDL to the smaller remnant. We F
DOI: 10.1021/acs.biochem.6b00946 Biochemistry XXXX, XXX, XXX−XXX
Article
Biochemistry for HDL, suggesting that plasma factors are less important to the reaction of neo HDL with HDL than with the other lipoproteins. Thus, the main fate of neo HDL-[3H]CE in plasma is the LPDS-independent association with HDL. This is further supported by the comparison of the half-times for the transfer of neo HDL-[3H]CE to serum from humans, WT mice, and LDL receptor-null mice (Table 1); the half-times decrease in the following order: human > LDL receptor-null mice ∼ WT mice (the same order in which the plasma HDL-C concentrations increase).33 However, the transfer of neo HDL-[3H]CE to LDL, which was nil in WT mice, is apparent in the LDL receptor-null mice (Supplementary Figure IX). The underlying reasons for these differences are likely the differences in particle numbers. First, mice have a HDL concentration higher than that of humans, so that the number of potential acceptors of neo HDL is greater. Second, plasma from LDLR−/− mice has a concentration of LDL higher than that of plasma from WT mice, i.e., more acceptors. Thus, the distribution of neo HDL among lipoproteins is driven by particle number, and given that the molarity of HDL is ∼10 times the molarity of all the other lipoproteins combined,34 HDL is the major serum acceptor of neo HDL. The higher HDL molarity would also explain the preferential transfer of neo HDL-phospholipids to HDL rather than other lipoproteins (Figure 2G−J). Neo HDL Is Less Stable Than HDL. Chaotropic perturbation with GdmCl shows that neo HDL is less stable than HDL (Supplementary Figures I and II). Previous studies that addressed the stability of HDL by chaotropic perturbation showed that apo AI release is concurrent with HDL fusion, which produces larger HDL particles.12,35,36 Similarly, neo HDL remnant particles fuse during CP, giving the larger particles observed in the SEC profile. The underlying cause of neo HDL instability is likely its low lipid content. Lipid-rich rHDL is more stable to chaotropes than lipid-poor rHDL;37 lipid-rich HDL2 is more stable than lipid-poor HDL3, and increasing the phospholipid content of HDL increases its stability.12 Thus, transfer of neo HDL-phospholipid to HDL produces the neo HDL remnant that would be expected to be even less stable. These data support a hypothetical model of the reaction of neo HDL with HDL (Figure 5). 1 Early phospholipid loss via transfer of neo HDL-phospholipid to HDL reduces the size of neo HDL while increasing that of HDL; in accordance with Kelvin’s law, phospholipid transfer is rapid because of the small size of neo HDL.2 Because of its increased instability, the remaining neo HDL remnant fuses with HDL, giving a larger HDL. To the best of our knowledge, this is the only observed instance of an intermediate in the process of one lipoprotein fusing with another lipoprotein in a biological setting. Our data show that the neo HDL → remnant → HDL reaction is stimulated by CETP and LCAT. The former may promote the reaction by the transfer of additional lipids, including neutral species from neo HDL to HDL. Although Clay and colleagues found that LCAT supports HDL fusion in vitro30 and neo HDL is a better LCAT substrate than HDL,15 no fusion mechanism was formulated from their data or ours. Cellular Uptake of Neo HDL-[3H]CE. Whereas neo HDL is a prominent in vitro product of SOF versus HDL,12 neo HDL is scarcely detectable in plasma of mice after injection with SOF.16 Moreover, the liver is the major site of uptake of plasma cholesterol after injection of SOF into mice. Thus, we compared the uptake of neo HDL-[ 3 H]CE in Huh7
Figure 5. Hypothetical model for the remodeling and metabolism of neo HDL (Neo).1 Neo HDL undergoes early size contraction to a remnant (R) via the transfer of phospholipid to HDL, which increases the size of HDL to HDL+; in accordance with Kelvin’s law, phospholipid transfer is rapid because of the small size of neo HDL.2 Because of its instability, the remaining neo HDL remnant (R) fuses with HDL, giving a larger HDL2+. In vivo, some neo and remnant HDL enter an early pathway of direct uptake (3 and 4, respectively), while the majority enters the plasma remodeling pathway (1, 2, and 5) and is removed via the HDL receptor pathway.
hepatocytes and CHO-KI cells and in CHO cells with disabled LDL receptors (ldlA7) and CHO ldlA7 cells expressing SR-B1, CHO[SR-B1]. SR-B1 and LDL receptors mediate selective HDL and LDL lipid uptake and uptake of CERM, the major cholesterol-containing SOF product, respectively.18,38 We found little neo HDL-[3H]CE uptake by CHO-KI cells and CHO-ldlA7 cells (Figure 3). The rate of uptake of neo HDL[3H]CE by SR-B1-expressing CHO cells was higher but still much lower than that by Huh7 cells. Immunoblot data showed no SR-B1 expression by CHO-KI and CHO-ldlA7 cells. To rule out SR-B1 as the neo HDL receptor in hepatic uptake, SR-B1 was transiently overexpressed in Huh7 cells. As shown in Figure 3E, SR-B1 overexpression profoundly increased the rate of HDL uptake but not that of neo HDL. Further, the rate of uptake of neo HDL by CHO-K1 was low and similar to that by CHO-ldlA7. Thus, neither LDLR nor SR-B1 is a likely receptor for neo HDL uptake, and an alternative receptor must be involved. Neo HDL-[3H]CE Metabolism in Vivo. The plasma kinetics of neo HDL-[3H]CE and HDL-[3H]CE were similar to half-times of 3.02 and 3.33 h, respectively, although the disappearance of plasma [3H]CE at the earliest time point was more profound for neo HDL-[3H]CE than for HDL-[3H]CE (Figure 4). However, there were differences in the attendant in vivo data for SEC plasma analysis and tissue uptake. The SEC for HDL-[3H]CE was similar at all postinjection time points, and it eluted as expected as HDL. However, none of the injected neo HDL-[3H]CE eluted as neo HDL but rather as HDL (Supplementary Figure X). Thus, in vivo metabolism and plasma clearance of neo HDL-CE were very rapid. The postinjection tissue localizations of neo HDL-[3H]CE and HDL-[3H]CE were also different at 30 min; the level of hepatically associated [3H]CE was much higher in mice injected with neo HDL-[3H]CE than in mice injected with HDL-[3H]CE. In contrast, in apo AI−/− mice, which have lower plasma HDL concentrations, HDL is cleared faster than neo HDL is (Supplementary Figure XII). These data provoke the second half of our model (Figure 5) in which we propose that there are two competing paths for hepatic neo HDL-[3H]CE G
DOI: 10.1021/acs.biochem.6b00946 Biochemistry XXXX, XXX, XXX−XXX
Article
Biochemistry disposal. In the first, shown as steps 3 and 4, some neo HDL[3H]CE and remnant, respectively, are rapidly removed by the liver before any interaction with other lipoproteins. In the second, steps 1, 2, and 5, neo HDL enters the remodeling pathway described above and is removed as a component of HDL; this may be mediated by multiple receptors, including SR-B1. Neo HDL versus Nascent HDL. Our studies of neo HDL provoke questions about the metabolic fate of other small HDL species such as the nascent HDL formed by the interaction of apo AI with macrophages,39 its in vitro analogue rHDL formed via the association of apo AI with phospholipids,40,41 and the remnant formed by the interaction of HDL with SR-B1. Like SOF, SR-B1 removes CE from HDL and forms smaller HDL that is depleted of CE.42 There are other parallels between SOF and SR-B1 activities: human HDL2 that is infused into SR-B1overexpressing mice is converted to smaller HDL, which is analogous to SOF-mediated neo HDL formation. Lastly, when smaller SR-B1-derived HDL or neo HDL is mixed with mouse plasma, each increases in size by associating with HDL.43 The in vivo fate of these particles has not been studied in detail, and this study demonstrates the feasibility of such studies and provides a protocol for such tests and a testable model. Both neo HDL and nascent HDL are putative vehicles for the disposal of plasma and cellular cholesterol, respectively. In vivo studies verifying the entry of nascent HDL and its in vitro models into the terminal RCT step, hepatic disposal, are needed.
■
AUTHOR INFORMATION
Corresponding Author
*Houston Methodist Research Institute, Room R11-217, 6670 Bertner Ave., Houston, TX 77030. E-mail: hjpownall@ HoustonMethodist.org. Telephone: (713) 449-4537. Funding
This work was supported in part by National Institutes of Health Grants HL056865 (H.J.P.) and HL129767 (H.J.P.) and the Bass Foundation (A.M.G.). Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Thanks to Dr. William Lagor for providing LDLR−/− mouse plasma, plasmids, and for his timely advice about HDL metabolism. Thanks to Dedipya Yelamanchili and Yaliu Yang for their expert technical assistance. This paper has been submitted in partial fulfillment of the requirements of P.J.R. to complete her Ph.D. in Integrative Molecular and Biomedical Sciences at Baylor College of Medicine.
■
ABBREVIATIONS apo, apolipoprotein; C, cholesterol; CE, cholesteryl ester; CERM, cholesteryl ester-rich microemulsion; CETP, cholesteryl ester transfer protein; CVD, cardiovascular disease; DPM, disintegrations per minute; DMPC, dimyristoylphosphatidylcholine; DTNB, dithiobis(2-nitrobenzoic acid); EV, elution volume; GdmCl, guanidinium hydrochloride; HDL, highdensity lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LF, lipid free; LPDS, lipoprotein-deficient serum; PC, phosphatidylcholine; RCT, reverse cholesterol transport; SEC, size exclusion chromatography; SR-B1, scavenger receptor class B member 1; SOF, serum opacity factor; TLP, total lipoprotein; TRCB, torcetrapib; VLDL, very low-density lipoprotein.
■
SIGNIFICANCE SOF and SR-B1 both extract the neutral lipids from HDL leaving a remnant. Although this has never been isolated from incubations of HDL with SR-B1-expressing cells, the remnant from the reaction of SOF versus HDL can be readily isolated and its biochemistry in plasma determined. Here we show that the SOF remnant, neo HDL, enters two disposal pathways, rapid, direct hepatic uptake and fusion with HDL followed by a slower hepatic uptake step. This is a testable mechanism for other native and putative plasma lipoproteins, including the nascent HDL formed by the interaction of apo AI with macrophage ABCA1 and Tangier HDL. Our data suggest but do not unequivocally prove that hepatic HDL remnant uptake does not involve SR-B1 or LDLR.
■
confirm the successful transfection of Huh7 cells with pAAV-EGFP-cB (PDF)
■
REFERENCES
(1) Gaziano, T. A. (2005) Cardiovascular disease in the developing world and its cost-effective management. Circulation 112, 3547−3553. (2) Bloom, D., Cafiero, E. T., Jane-Llopis, E., et al. (2011) The Global Economic Burden of Noncommunicable Diseases, World Economic Burden Forum, Geneva. (3) Barquera, S., Pedroza-Tobias, A., Medina, C., Hernandez-Barrera, L., Bibbins-Domingo, K., Lozano, R., and Moran, A. E. (2015) Global Overview of the Epidemiology of Atherosclerotic Cardiovascular Disease. Arch. Med. Res. 46, 328−338. (4) Castelli, W. P., Garrison, R. J., Wilson, P. W., Abbott, R. D., Kalousdian, S., and Kannel, W. B. (1986) Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 256, 2835−2838. (5) Rader, D. J., and Hovingh, G. K. (2014) HDL and cardiovascular disease. Lancet 384, 618−625. (6) Rye, K. A., Bursill, C. A., Lambert, G., Tabet, F., and Barter, P. J. (2008) The metabolism and anti-atherogenic properties of HDL. J. Lipid Res. 50 (Suppl.), S195−S200. (7) Krause, B. R., and Remaley, A. T. (2013) Reconstituted HDL for the acute treatment of acute coronary syndrome. Curr. Opin. Lipidol. 24, 480−486. (8) Toth, P. P., Barylski, M., Nikolic, D., Rizzo, M., Montalto, G., and Banach, M. (2014) Should low high-density lipoprotein cholesterol
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.6b00946. Primary data for chaotropic perturbation of HDL and neo HDL; data showing the absence of SOF activity in neo HDL and the absence of an effect of lipoproteindeficient serum on neo HDL structure; data showing that neo HDL does not interact or interacts minimally with low- and very low-density lipoproteins and that inhibition of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein inhibits the transfer of neo HDL-CE to other lipoproteins; SEC data showing that in WT mice neo HDL-CE fuses with HDL and that turnover of HDL-CE and neo HDL-CE in apo AI-null mice is fast (minutes); and fluorescence images that H
DOI: 10.1021/acs.biochem.6b00946 Biochemistry XXXX, XXX, XXX−XXX
Article
Biochemistry (HDL-C) be treated? Best Pract Res. Clin Endocrinol Metab 28, 353− 368. (9) Courtney, H. S., Zhang, Y. M., Frank, M. W., and Rock, C. O. (2005) Serum opacity factor, a streptococcal virulence factor that binds to apolipoproteins A-I and A-II and disrupts high density lipoprotein structure. J. Biol. Chem. 281, 5515−5521. (10) Oram, J. F., Lawn, R. M., Garvin, M. R., and Wade, D. P. (2000) ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J. Biol. Chem. 275, 34508− 34511. (11) Kang, M. H., Singaraja, R., and Hayden, M. R. (2010) Adenosine-triphosphate-binding cassette transporter-1 trafficking and function. Trends Cardiovasc. Med. 20, 41−49. (12) Pownall, H. J., Hosken, B. D., Gillard, B. K., Higgins, C. L., Lin, H. Y., and Massey, J. B. (2007) Speciation of human plasma highdensity lipoprotein (HDL): HDL stability and apolipoprotein A-I partitioning. Biochemistry 46, 7449−7459. (13) Han, M., Gillard, B. K., Courtney, H. S., Ward, K., Rosales, C., Khant, H., Ludtke, S. J., and Pownall, H. J. (2009) Disruption of human plasma high-density lipoproteins by streptococcal serum opacity factor requires labile apolipoprotein A-I. Biochemistry 48, 1481−1487. (14) Gillard, B. K., Courtney, H. S., Massey, J. B., and Pownall, H. J. (2007) Serum opacity factor unmasks human plasma high-density lipoprotein instability via selective delipidation and apolipoprotein A-I desorption. Biochemistry 46, 12968−12978. (15) Tchoua, U., Rosales, C., Tang, D., Gillard, B. K., Vaughan, A., Lin, H. Y., Courtney, H. S., and Pownall, H. J. (2010) Serum opacity factor enhances HDL-mediated cholesterol efflux, esterification and anti inflammatory effects. Lipids 45, 1117−1126. (16) Rosales, C., Tang, D., Gillard, B. K., Courtney, H. S., and Pownall, H. J. (2011) Apolipoprotein E mediates enhanced plasma high-density lipoprotein cholesterol clearance by low-dose streptococcal serum opacity factor via hepatic low-density lipoprotein receptors in vivo. Arterioscler., Thromb., Vasc. Biol. 31, 1834−1841. (17) Brown, M. L., Inazu, A., Hesler, C. B., Agellon, L. B., Mann, C., Whitlock, M. E., Marcel, Y. L., Milne, R. W., Koizumi, J., Mabuchi, H., et al. (1989) Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature 342, 448−451. (18) Acton, S., Rigotti, A., Landschulz, K. T., Xu, S., Hobbs, H. H., and Krieger, M. (1996) Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271, 518−520. (19) Pownall, H. J., Courtney, H. S., Gillard, B. K., and Massey, J. B. (2008) Properties of the products formed by the activity of serum opacity factor against human plasma high-density lipoproteins. Chem. Phys. Lipids 156, 45−51. (20) Gillard, B. K., Rosales, C., Pillai, B. K., Lin, H. Y., Courtney, H. S., and Pownall, H. J. (2010) Streptococcal serum opacity factor increases the rate of hepatocyte uptake of human plasma high-density lipoprotein cholesterol. Biochemistry 49, 9866−9873. (21) Weisgraber, K. H., and Shinto, L. H. (1991) Identification of the disulfide-linked homodimer of apolipoprotein E3 in plasma. Impact on receptor binding activity. J. Biol. Chem. 266, 12029−12034. (22) Schumaker, V. N., and Puppione, D. L. (1986) Sequential flotation ultracentrifugation. Methods Enzymol. 128, 155−170. (23) Courtney, H. S., Hasty, D. L., Li, Y., Chiang, H. C., Thacker, J. L., and Dale, J. B. (1999) Serum opacity factor is a major fibronectinbinding protein and a virulence determinant of M type 2 Streptococcus pyogenes. Mol. Microbiol. 32, 89−98. (24) Tall, A. R. (1986) Plasma lipid transfer proteins. J. Lipid Res. 27, 361−367. (25) Jin, W., Marchadier, D., and Rader, D. J. (2002) Lipases and HDL metabolism. Trends Endocrinol. Metab. 13, 174−178. (26) Mason, J. T., Broccoli, A. V., and Huang, C. (1981) A method for the synthesis of isomerically pure saturated mixed-chain phosphatidylcholines. Anal. Biochem. 113, 96−101. (27) Gillard, B. K., Raya, J. L., Ruiz-Esponda, R., Iyer, D., Coraza, I., Balasubramanyam, A., and Pownall, H. J. (2013) Impaired lipoprotein processing in HIV patients on antiretroviral therapy: aberrant high-
density lipoprotein lipids, stability, and function. Arterioscler., Thromb., Vasc. Biol. 33, 1714−1721. (28) Pattnaik, N. M., Montes, A., Hughes, L. B., and Zilversmit, D. B. (1978) Cholesteryl ester exchange protein in human plasma isolation and characterization. Biochim. Biophys. Acta, Lipids Lipid Metab. 530, 428−438. (29) Bruce, C., and Tall, A. R. (1995) Cholesteryl ester transfer proteins, reverse cholesterol transport, and atherosclerosis. Curr. Opin. Lipidol. 6, 306−311. (30) Clay, M. A., Pyle, D. H., Rye, K. A., and Barter, P. J. (2000) Formation of spherical, reconstituted high density lipoproteins containing both apolipoproteins A-I and A-II is mediated by lecithin:cholesterol acyltransferase. J. Biol. Chem. 275, 9019−9025. (31) Thomson, S. W. (1871) On the equilibrium of vapour at curved surface of a liquid. Philos. Mag. 42, 5. (32) Pownall, H. J., Bick, D. L., and Massey, J. B. (1991) Spontaneous phospholipid transfer: development of a quantitative model. Biochemistry 30, 5696−5700. (33) Ishibashi, S., Herz, J., Maeda, N., Goldstein, J. L., and Brown, M. S. (1994) The two-receptor model of lipoprotein clearance: tests of the hypothesis in ″knockout″ mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc. Natl. Acad. Sci. U. S. A. 91, 4431−4435. (34) Smith, L. C., Massey, J. B., Sparrow, J. T., Gotto, A. M., Jr., and Pownall, H. J. (1983) Structure and dynamics of human plasma lipoproteins. In Supramolecular Structure and Function (Pifat, G., and Herak, J. N., Eds.) pp 205−243, Springer, Berlin. (35) Pownall, H. J. (2005) Remodeling of human plasma lipoproteins by detergent perturbation. Biochemistry 44, 9714−9722. (36) Jayaraman, S., Gantz, D. L., and Gursky, O. (2005) Kinetic stabilization and fusion of apolipoprotein A-2:DMPC disks: comparison with apoA-1 and apoC-1. Biophys. J. 88, 2907−2918. (37) Jonas, A., Wald, J. H., Toohill, K. L., Krul, E. S., and Kezdy, K. E. (1990) Apolipoprotein A-I structure and lipid properties in homogeneous, reconstituted spherical and discoidal high density lipoproteins. J. Biol. Chem. 265, 22123−22129. (38) Gillard, B. K., Rodriguez, P. J., Fields, D. W., Raya, J. L., Lagor, W. R., Rosales, C., Courtney, H. S., Gotto, A. M., Jr., and Pownall, H. J. (2016) Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 1861, 196−204. (39) Lyssenko, N. N., Nickel, M., Tang, C., and Phillips, M. C. (2013) Factors controlling nascent high-density lipoprotein particle heterogeneity: ATP-binding cassette transporter A1 activity and cell lipid and apolipoprotein AI availability. FASEB J. 27, 2880−2892. (40) Matz, C. E., and Jonas, A. (1982) Micellar complexes of human apolipoprotein A-I with phosphatidylcholines and cholesterol prepared from cholate-lipid dispersions. J. Biol. Chem. 257, 4535−4540. (41) Pownall, H. J., Van Winkle, W. B., Pao, Q., Rohde, M., and Gotto, A. M., Jr. (1982) Action of lecithin:cholesterol acyltransferase on model lipoproteins. Preparation and characterization of model nascent high density lipoprotein. Biochim. Biophys. Acta, Lipids Lipid Metab. 713, 494−503. (42) Webb, N. R., Cai, L., Ziemba, K. S., Yu, J., Kindy, M. S., van der Westhuyzen, D. R., and de Beer, F. C. (2002) The fate of HDL particles in vivo after SR-BI-mediated selective lipid uptake. J. Lipid Res. 43, 1890−1898. (43) Webb, N. R., de Beer, M. C., Asztalos, B. F., Whitaker, N., van der Westhuyzen, D. R., and de Beer, F. C. (2004) Remodeling of HDL remnants generated by scavenger receptor class B type I. J. Lipid Res. 45, 1666−1673.
I
DOI: 10.1021/acs.biochem.6b00946 Biochemistry XXXX, XXX, XXX−XXX
