The role of scavenger receptors in cardiovascular disease and related disorders.
Atherosclerosis is a disease caused by plaque build-up in the artery wall, which ultimately results in reduced blood flow due to narrowing of the arteries. Plaque build-up results from the accumulation of cholesterol and other cellular debris. Cholesterol is carried through our bloodstream in vehicles called lipoproteins. Low density lipoproteins (LDL) – the “bad cholesterol” – carry cholesterol from the liver to peripheral tissues (such as the arterial wall). High density lipoproteins (HDL) – the “good cholesterol” – transport cholesterol from peripheral tissues back to the liver for excretion in a process called “reverse cholesterol transport.”
While HDL protects against atherosclerosis due to its role in reducing oxidative damage, preventing inflammation and promoting endothelial function, our lab is very interested in the role that HDL plays in reverse cholesterol transport and whole body cholesterol disposal.
Scavenger receptor class B type I (SR-BI), the most physiologically relevant HDL receptor, is highly expressed in the liver and plays a key role in mediating the delivery of HDL-C to the liver for excretion. This process termed “selective uptake” requires two steps: (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. Genetic mouse models demonstrate that SR-BI protects against atherosclerosis. Further, the recent discovery of SR-BI mutations in patients with high HDL-C levels strongly supports a critical role of SR-BI in facilitating the flux of cholesterol out of the body.
In order to develop novel therapeutic strategies that treat hypercholesterolemia and its associated pathologies such as atherosclerosis, it is critical that we understand the mechanisms that regulate receptor-ligand interactions at the end of reverse cholesterol transport. A better understanding of the interaction between SR-BI and HDL will allow us to gain novel insight into mechanisms that facilitate the efficient clearance of HDL-C via SR-BI-mediated selective uptake of HDL lipids.
To accomplish these goals, our laboratory is currently studying the following:
- The molecular architecture of the extracellular domain of SR-BI (using novel fluorescence strategies and other biochemical techniques);
- The oligomeric properties of SR-BI;
- The mechanisms of HDL-CE delivery and hydrolysis at the plasma membrane
- The impact of modified HDL on selective uptake of HDL lipids.
Daisy Sahoo and Victor A. Drover (2006). The role of scavenger receptors in signaling, inflammation and atherosclerosis in Advances in Biochemistry in Health Disease book series, Biochemistry of Atherosclerosis, ed. by S. Kaur Cheema, Springer, New York. In press.
Peer-Reviewed Papers of Interest
Alexandra C. Chadwick & Daisy Sahoo (2013) Functional genomics of the human high-density lipoprotein receptor scavenger receptor BI: an old dog with new tricks. Curr. Opin. Endocrinol. Diabetes Obes. 20:124-131. PMID: 23403740.
Alexandra C. Chadwick & Daisy Sahoo (2012) Functional characterization of newly-discovered mutations in human SR-BI. PLoS ONE. 7, e45660. PMID: 23029167.
Gabriella A. Papale, Paul J. Hanson. & Daisy Sahoo (2011) Extracellular disulfide bonds support scavenger receptor BI-mediated cholesterol transport. Biochemistry. 50, 6245-6254. PMID: 21675794.
Jessica P. Otis, Daisy Sahoo, Victor A. Drover, Eric C-L. Yen, & Hannah V. Carey (2011) Cholesterol and lipoprotein dynamics in a hibernating mammal. PLoS ONE. 6, e29111. PMID: 22195001; PMCID: PMC3240636.
Gabriella A. Papale, Kay Nicholson, Paul J. Hanson, Mitja Pavlovic, Victor A. Drover & Daisy Sahoo (2010) Hydrophobic regions in the extracellular domain of scavenger receptor BI play a key role in mediating HDL-cholesterol transport. Arch. Biochem. Biophys. 496, 132-139. PMID:20219439; PMCID: PMC2853188.
Victor A. Drover, David V. Nguyen, Claire C. Bastie, Yolanda F. Darlington, Nada A. Abumrad, Jeffrey E. Pessin, Erwin London, Daisy Sahoo & Michael C. Phillips (2008) CD36 mediates both cellular uptake of very long chain fatty acids and their intestinal absorption in mice. J. Biol. Chem. 283, 13108-13115. PMID: 18332148; PMCID: PMC2442355.
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. 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.
The goal of my research is to understand how modification to HDL impairs HDL function.
- Recipient of American Heart Association Post-doctoral Fellowship
- Winner of 2011 Best Poster Prize (Graduate School of Biomedical Sciences, MCW)
- Recipient of Finn Wold Travel Award and Protein Science Young Investigator Travel Grant, Symposium of the Protein Society, 2014
My projects focus on understanding structural characteristics of the HDL receptor, SR-BI, in order to better understand and optimize removal of circulating cholesterol.
- Recipient of Young Investigator Travel Award, 2014 ATVB Conference
Sahoo Lab Alumni
Gabriella Kartz (nee Papale)
Current position: Post-doctoral fellow, Blood Center of Wisconsin