Objective-High-density lipoprotein (HDL) cholesteryl esters (CE) are taken up by liver and adrenals selectively, ie, independent from particle internalization. Class B type I scavenger receptor (SR-BI) mediates this uptake in vitro. The role of SR-BI in HDL metabolism was explored in mice. Methods and Results-Mice with a mutation in the SR-BI gene (SR-BI KO) and wild-type (WT) littermates were used.Mutants had increased HDL cholesterol. HDL was labeled with 125 I (protein) and [ 3 H] (CE). After HDL injection, blood samples were drawn and finally the mice were euthanized. In WT, the plasma decay of HDL-associated [ 3 H] is faster compared with 125 I and this represents whole-body selective CE uptake. In SR-BI KO, the decay of both tracers is similar, yielding no selective CE removal. In WT liver and adrenals, uptake of [ 3 H] is higher than 125 I, showing selective uptake. In SR-BI KO, liver uptake of [ 3 H] and 125 I are similar, proposing no selective HDL CE uptake. In SR-BI KO adrenals, selective uptake is reduced; however, even in the absence of SR-BI, this uptake is detected using WT-HDL. Key Words: HDL Ⅲ SR-BI Ⅲ cholesterol Ⅲ liver Ⅲ receptor H igh-density lipoprotein (HDL) plays a critical role in cholesterol homeostasis. 1 HDL presumably removes cholesterol from peripheral tissues. 1,2 After esterification in plasma, HDL-associated cholesteryl esters (CE) are delivered to other lipoprotein fractions or to tissues. 1,2 One mechanism that mediates the delivery of HDL-associated CE to organs is the selective lipid uptake pathway. 3 In this process, HDL CE are internalized by cells independently from the uptake of the HDL particle. This selective lipid uptake appears to be important for the transport of cholesterol to steroidogenic tissues for hormone synthesis and to the liver. 3 In this central organ of lipid metabolism, HDL cholesterol is secreted into bile, used for bile acid synthesis, or packaged and secreted in newly synthesized lipoproteins. 2 This HDL-mediated transport of cholesterol from extrahepatic tissues to the liver is designated reverse cholesterol transport. 1 The class B type I scavenger receptor (SR-BI) is a cell surface HDL receptor that binds HDL. 4 In cultured cells, SR-BI mediates the selective HDL CE uptake. In rodents, SR-BI is most abundantly expressed in liver and steroidogenic tissues, 4 which are those tissues most actively engaged in selective lipid uptake in vivo. 3,5 In mice, hepatic overexpression of SR-BI reduces plasma HDL and increases biliary cholesterol. 6 In contrast, rodents with a targeted null mutation in the SR-BI gene have an increase in plasma HDL. 7 Taken together, evidence has been presented that SR-BI may be a physiologically relevant HDL receptor in vivo. Conclusions-SR-BIThe role of SR-BI in HDL metabolism was explored in mice with an attenuated expression of this receptor in liver and adrenals. 8 Studies using radiolabeled HDL showed that a 53% decrease in hepatic SR-BI expression is associated with a 47% reduction in HDL selective CE uptake by the liver...

wall. After esterifi cation in plasma, HDL-associated cholesteryl esters (CE) are delivered to other lipoprotein fractions or tissues ( 1, 2 ). One mechanism that mediates the direct delivery of HDL-associated CE to organs is the selective lipid uptake pathway ( 2 ). In this process, HDL CE is internalized by cells independently of the uptake of the HDL holo-particle. This selective lipid uptake appears to be important for the transport of cholesterol to steroidogenic tissues for hormone biosynthesis and to the liver. In the liver, HDL-derived cholesterol can be secreted into bile, used for bile acid synthesis, or packaged and secreted in newly synthesized lipoproteins.Scavenger receptors mediate the cellular uptake of lipoproteins ( 3, 4 ). Scavenger receptor class B type I (SR-BI) and cluster of differentiation 36 (CD36) are members of class B of this family ( 3, 5 ). As plasma membrane-associated proteins, structurally both molecules comprise extracellular loops that are anchored in the membrane by transmembrane domains adjacent to short cytoplasmic tails. A high degree of sequence homology is detected throughout the extracellular loop domains between SR-BI and CD36; however, the cytoplasmic and the transmembrane domains have limited sequence similarity ( 4 ).SR-BI is expressed abundantly in the liver and steroidogenic tissues ( 3 ). This receptor binds HDL with high affi nity and mediates selective uptake of HDL CE in the liver and adrenals ( 6 ). In mice, hepatic SR-BI overexpression promotes selective HDL CE uptake by the liver ( 7 ). In contrast, mice