The role of scavenger receptor BI (SR-BI) in the selective uptake and hydrolysis of cholesteryl esters.
Epidemiological studies show that the risk for developing coronary heart disease (such as atherosclerosis) is inversely related to plasma concentrations of high density lipoproteins (HDL). HDL may inhibit the development and progression of atherosclerosis by several mechanisms including reductions in oxidative damage, endothelial dysfunction and inflammation. However, it is believed that HDL is atheroprotective, primarily by virtue of its role in reverse cholesterol transport whereby cholesterol is transferred from peripheral tissues to HDL and then transported to the liver for bile acid synthesis and secretion of cholesterol into bile, or to steroidogenic tissues for steroid hormone synthesis. Development of macrophage "foam cells" that contain massive amounts of cholesteryl ester (CE) is a hallmark of both early and late atherosclerotic lesions. In the plasma, CE is transported by low density lipoproteins (LDL) and HDL and the proportion of cholesterol in each particle is a strong indicator of foam cell and atherosclerotic lesion formation.
Scavenger receptor class B type I (SR-BI), an 82 kDa cell surface glycoprotein, was characterized as the most physiologically relevant HDL receptor by virtue of its ability to mediate the selective uptake of HDL-CE. SR-BI-mediated selective uptake of HDL-CE is a two-step process: (i) HDL must bind to the extracellular domain of SR-BI and (ii) lipid alone is transferred from HDL to the plasma membrane, without holoparticle uptake. SR-BI is highly expressed in the liver, as well as in adrenals, ovaries and testes, steroidogenic tissues that exhibit high rates of HDL-CE selective uptake. Mice with a disrupted SR-BI gene have increased plasma HDL cholesterol levels and reduced neutral lipid stores in the adrenal gland and ovary. Complementary studies revealed that overexpression of SR-BI in transgenic mice or by adenoviral infection resulted in decreased HDL cholesterol levels and increased hepatic HDL-CE selective uptake. It was also demonstrated that purified SR-BI reconstituted into multilamellar vesicles could mediate the selective uptake of HDL-CE in the absence of other proteins. Furthermore, SR-BI expression induces dramatic changes in membrane organization and composition which may affect the efficiency of CE metabolism. Therefore, SR-BI plays a crucial role in mediating HDL-CE selective uptake, both in vivo and in vitro.
Understanding of how SR-BI mediates the selective uptake, hydrolysis and metabolism of HDL-CE is key in gaining insight into its atheroprotective role. We hypothesize that the structural organization of SR-BI, in addition to its role in mediating plasma membrane morphology, facilitates the movement of HDL-CE into the membrane and targeting to a hydrolase. The anticipated findings from our studies will improve our understanding of how SR-BI mediates the efficiency of selective uptake and may identify novel therapeutic strategies for treating hypercholesterolemia and its associated pathologies such as atherosclerosis.
Our laboratory is currently studying the following:
1. The structural organization of SR-BI in the plasma membrane (using fluorescence resonance energy transfer microscopy and fluorescence quenching, in addition to standard biochemical techniques);
2. The role of plasma membrane phospholipids in the efficiency of selective uptake of HDL-CE using mass spectrometry and electron microscopy;
3. The mechanisms of HDL-CE delivery and hydrolysis at the plasma membrane
4. The in vivo role of SR-BI structure/function mutations by adenoviral infection of SR-BI knock-out mice.
Daisy Sahoo, Yinan Peng, Jeff R. Smith, Yoland Darlington, and Margery A. Connelly (2007) Scavenger receptor class B, type I (SR-BI) homo-dimerizes via its C-terminal region: fluorescence resonance energy transfer analysis. Biochim Biophys Acta. 1771:818-29.
Daisy Sahoo, Yolanda F. Darlington, Diana Pop, David L. Williams & Margery A. Connelly (2007) Scavenger receptor class B type I (SR-BI) assembles into detergent-sensitive dimers and tetramers. Biochim Biophys Acta. 1771:807-17.
Sajesh Parathath, Daisy Sahoo, Yolanda F. Darlington, Yinan Peng, Heidi L. Collins, George H. Rothblat, David, L. Williams & Margery A. Connelly (2004) Glycine 420 near the C-terminal transmembrane domain of SR-BI is critical for proper delivery and metabolism of high density lipoprotein cholesteryl ester. J. Biol. Chem. 279, 24976-24985.
Victor Drover, Mohammed Ajmal, Fatiha Nassir, Nicholas O. Davidson, Amdromeda M. Nauli, Daisy Sahoo, Patrick Tso and Nada A. Abumrad (2005) CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood. J. Clin. Invest. 115: 1290-1297.
Daisy Sahoo, Tim C. Trischuk, Teddy Chan, Victor A. Drover, Samuel Ho, Giovanna Chimini, Luis B. Agellon, Ricky Agnihotri, Gordon A. Francis, & Richard Lehner (2004) ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from primary rat and mouse hepatocytes. J. Lipid Res. 45, 1122-1131.
J. Boucher, Tanya A. Ramsamy, Sylvie Braschi, Daisy Sahoo, Tracey A. Neville & Daniel L. Sparks (2004) Apolipoprotein A-II regulates HDL stability and affects hepatic lipase association and activity. J. Lipid Res. 45, 849-858.
Daisy Sahoo, Paul M. M. Weers, Robert O. Ryan & Vasanthy Narayanaswami (2002) Lipid-triggered conformational switch of apolipophorin III helix bundle to an extended helix organization. J. Mol. Bol. 321, 201-214.
Daisy Sahoo, Vasanthy Narayanaswami, Cyril M. Kay & Robert O. Ryan (2000) Pyrene excimer fluorescence: A spatially sensitive probe to monitor lipid-induced helical rearrangement of apolipophorin III. Biochemistry 39, 6594-6601.
Jianjun Wang, Daisy Sahoo, Brian D. Sykes & Robert O. Ryan (1998) NMR evidence for a conformational adaptation of apolipophorin III upon lipid association. Biochem. Cell Biol. 76, 276-283.
Daisy Sahoo, Vasanthy Narayanaswami, Cyril M. Kay & Robert O. Ryan (1998) Fluorescence studies of exchangeable apolipoprotein-lipid interactions: Superficial association of apolipophorin III with lipoprotein surfaces. J. Biol. Chem. 273, 1403-1408.
Jianjun Wang, Daisy Sahoo, Dean Schieve, Stephane M. Gagné, Brian D. Sykes & Robert O. Ryan (1997) Multidimensional NMR studies of an exchangeable apolipoprotein and its interactions with lipids. Techniques in Protein Chemistry VIII, 427-438.