Scavenger receptor class B type I (SR-BI) mediates the selective transfer of cholesteryl ester from HDL to cells. We previously established that SR-BI overexpressed in livers of apolipoprotein A-I-deficient mice processes exogenous human HDL 2 to incrementally smaller HDL particles. When mixed with normal mouse plasma either in vivo or ex vivo, SR-BI-generated HDL "remnants" rapidly remodel to form HDL-sized lipoproteins. In this study, we analyzed HDLs throughout the process of HDL remnant formation and investigated the mechanism of conversion to larger particles. Upon interacting with SR-BI, ␣ -migrating HDL 2 is initially converted to a pre ␣ -migrating particle that is ultimately processed to a smaller ␣ -migrating HDL remnant. SR-BI does not appear to generate pre ␤ -1 HDL particles. When incubated with isolated lipoprotein fractions, HDL remnants are converted to lipoprotein particles corresponding in size to the particle incubated with the HDL remnant. HDL remnant conversion is not altered in phospholipid transfer protein (PLTP)-deficient mouse plasma or by the addition of purified PLTP. Although LCAT-deficient plasma promoted only partial conversion, this deficiency was attributable to the nature of HDL particles in LCAT ؊ / ؊ mice rather than to a requirement for LCAT in the remodeling process. We conclude that HDL remnants, generated by SR-BI, are converted to larger particles by rapidly reassociating with existing HDL particles in an enzyme-independent manner. -Webb, N. R., M. C. de Beer, B. F. Asztalos, N. Whitaker, D. R. van der Westhuyzen, and F. C. de Beer. Remodeling of HDL remnants generated by scavenger receptor class B type I.

The HDL receptor scavenger receptor class B type I (SR-BI) binds HDL and mediates the selective uptake of cholesteryl ester. We previously showed that remnants, produced when human HDL 2 is catabolized in mice overexpressing SR-BI, become incrementally smaller, ultimately consisting of small ␣ -migrating particles, distinct from pre ␤ HDL. When mixed with mouse plasma, some remnant particles rapidly increase in size by associating with HDL without the mediation of cholesteryl ester transfer protein, LCAT, or phospholipid transfer protein. Here, we show that processing of HDL 2 by SR-BI-overexpressing mice resulted in the preferential loss of apolipoprotein A-II (apoA-II). Short-term processing generated two distinct, small ␣ -migrating particles. One particle (8.0 nm diameter) contained apoA-I and apoA-II; the other particle (7.7 nm diameter) contained only apoA-I. With extensive SR-BI processing, only the 7.7 nm particle remained. Only the 8.0 nm remnants were able to associate with HDL. Compared with HDL 2 , this remnant was more readily taken up by the liver than by the kidney. We conclude that SR-BI-generated HDL remnants consist of particles with or without apoA-II and that only those containing apoA-II associate with HDL in an enzyme-independent manner. Extensive SR-BI processing generates small apoA-II-depleted particles unable to reassociate with HDL and readily taken up by the liver. This represents a pathway by which apoA-I and apoA-II catabolism are segregated.

Objective-The purpose of this study was to investigate the interaction of SAA and SR-BI in remodeling of acute phase HDL (AP HDL). Methods and Results-We used SAA and SR-BI adenoviral vector expression models to study the interaction between these entities. SR-BI processing of mouse AP HDL generated progressively smaller discreet HDL particles with distinct apolipoprotein compositions. SR-BI actions segregated apolipoproteins with the smallest particles containing only apoA-I. Larger remnants contained apoA-I, apoA-II, and SAA. Small apoA-I only particles failed to associate with preformed HDL, whereas larger remnants readily did. The presence of SAA on SR-BI-processed HDL particles propelled apoA-I to a small lipid-poor form and accelerated apoA-I catabolism. Key Words: Conclusions-Datantimate associations exist between atherosclerosis and inflammation. The atherosclerotic process itself has features of chronic inflammation. 1 Furthermore, the process of atherosclerosis is markedly accelerated by chronic inflammatory disease states such as rheumatoid arthritis. 2 Perhaps most notable among the plethora of metabolic changes that affect lipid and lipoproteins during inflammation are the structural and metabolic alterations of HDL. 3 Serum amyloid A protein (SAA) becomes a major apolipoprotein of HDL during the acute phase and can replace apoA-I as the major HDL apolipoprotein. 3 Concomitant with SAA induction is a decline in plasma HDL cholesterol and apoA-I levels. 3 Notable lipid changes occur, and HDL becomes generally enriched in triglycerides. 4 The scavenger receptor class B type I (SR-BI) plays an important role in the metabolism of high-density lipoprotein (HDL). 5 It binds HDL with high affinity and by selective lipid uptake mediates the movement of cholesterol ester from the hydrophobic HDL core to the cell. 5 SR-BI-mediated selective lipid uptake generates incrementally smaller and denser HDL particles (HDL remnants). 6 With respect to normal human HDL, these remnants are not rapidly cleared from the circulation but rather remodel to form large HDL particles by association with existing lipoprotein particles, preferably HDL. 6 -8 A portion of the HDL remnant apolipoproteins is directed toward catabolism. 9 We used 2 model systems to study the interactions between SR-BI and SAA-containing acute phase HDL (AP HDL). The first is an established model where the metabolic fate of radiolabeled AP HDL in mice over expressing SR-BI is evaluated. 6 -8 The second involves monitoring the effect of dual SR-BI and SAA adenoviral expression on endogenous HDL metabolism. The latter approach mimics the acute phase as SAA is predominantly produced in the liver. Data indicate that SR-BI action segregates AP HDL apolipoprotein catabolism. Discrete AP HDL remnant particles with distinct apolipoprotein compositions are generated. The presence of SAA on AP HDL remnants tends to propel apoA-I to small lipid poor forms potentially impacting efflux while at the same time accelerating apoA-I catabolism.

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