SR-BI Selective Lipid Uptake

Abstract

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.

Nascent HDL formation by hepatocytes is reduced by the concerted action of serum amyloid A and endothelial lipase

“…4A ). These fi ndings contrast to what we have previously shown to occur with HDL core remodeling by SR-BI ( 19 ) and repeat here for illustrative purposes ( Fig. 4B ).…”

“…Whether the presence of SAA on HDL can modulate HDL remodeling by EL has not been investigated. Previous studies from our laboratory showed that in the presence of SAA, perturbation of HDL core and surface lipid by scavenger receptor class B type I (SR-BI) leads to generation of small, lipid-depleted apoA-I that is susceptible to catabolism ( 19 ). In this study, we carried out in vitro and in vivo studies to investigate whether the presence of SAA infl uences EL-mediated metabolism of HDL.…”

“…with 2.5 U heparin in 100 l PBS 30 min prior to plasma collection. In the case of the AdSAA + AdSR-BI experiments, the dose of AdSR-BI increased hepatic SR-BI expression ‫ف‬ 3-fold, which resulted in a ‫ف‬ 50% decline in HDL levels, whereas hepatic SAA was increased ‫ف‬ 8-fold without impacting HDL levels when expressed by itself ( 19 ).…”

Effects of serum amyloid A on the structure and antioxidant ability of high-density lipoprotein

“…It was also confirmed by that serum SAA levels were correlated with relative lag times in all samples ( Figure 8 D). In general, HDL-Cho levels in patients with severe inflammation are lower than that in normal subjects, because of accelerated catabolism of SAA-HDL [ 1 , 29 ]. HDL-Cho concentrations within the High SAA group were 22% lower compared with those observed within Low SAA group ( Figure 8 C).…”