Sahoo Laboratory

Location

Health Research Center

H4930

General Interests

Lipoprotein Metabolism, Scavenger Receptors, Cardiovascular Disease, Diabetes, Obesity

View Daisy Sahoo, PhD Bio

Research Areas

The role of scavenger receptors in cardiovascular disease and related metabolic 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. 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.

Our laboratory is trying to answer the following questions:

What are key structural features of SR-BI that facilitate HDL-cholesterol transport?
Can we use biophysical and high-resolution techniques to gain structural information about full-length SR-BI and/or its extracellular/transmembrane domains?
What is the oligomeric organization of SR-BI and how does that influence HDL-cholesterol transport?
How does oxidation of HDL impact its cardio-protective functions and the progression of atherosclerosis?
How does SR-BI facilitate cholesterol delivery into adipocytes?
What happens when HDL-cholesterol gets hydrolyzed in cells?
How does HDL impact beta cell function and diabetes?

Techniques

Research in the Sahoo laboratory relies on several techniques that will teach the following:

Cell culture-based cholesterol transport assays
Lipid and lipoprotein analyses
Signal transduction
Protein-protein interactions using biophysical/biochemical methods
Fluorescence methodologies (e.g. spin labeling, FRET)
Live cell imaging
Confocal microscopy
Mass Spectrometry (via collaboration)
NMR (via collaboration)
EPR (via collaboration)
In vivo mouse models that express SR-BI mutants
In vivo reverse cholesterol transport and atherosclerosis studies

Current Members

Kay Nicholson

kaynicholson

Research Associate II
knichols@mcw.edu

Oversight of all lab activities including laboratory safety, ordering, and training of undergraduate, medical and graduate students.

Darcy Knaack

darcyknaack

Graduate Student (IDP program)
dknaack@mcw.edu

The roles of PCPE2 and SR-BI in mediating cholesterol transport in adipocytes

Sarah Proudfoot, PhD

sarahproudfoot

Graduate Student (IDP program)
sproudfoot@mcw.edu

Correlating features of the extracellular domain of SR-BI to its HDL-cholesterol transport functions

Gage Stuttgen

Graduate Student (IDP program)
gstuttgen@mcw.edu

Understanding how nutrient sensing mechanisms through G protein-coupled receptors influence reverse cholesterol transport and lead to the progression of atherosclerosis and cardiovascular disease.

Hayley Powers

Graduate Student (MSTP MD/PhD program)
hpowers@mcw.edu

Elucidating the structure and oligomeric properties of SR-BI, the HDL receptor

Alumni/Former Trainees

Gabriella Papale, PhD (2008-2012)
Alexandra Chadwick, PhD (2010-2015)
Rebecca Schill, PhD (2012-2018)

Modification of HDL by reactive aldehydes alters select cardioprotective functions of HDL in macrophages.

(Schill RL, Knaack DA, Powers HR, Chen Y, Yang M, Schill DJ, Silverstein RL, Sahoo D.) FEBS J. 2020 02;287(4):695-707 PMID: 31386799 PMCID: PMC7002295 SCOPUS ID: 2-s2.0-85070750063 08/07/2019
Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses.

(Chen Y, Yang M, Huang W, Chen W, Zhao Y, Schulte ML, Volberding P, Gerbec Z, Zimmermann MT, Zeighami A, Demos W, Zhang J, Knaack DA, Smith BC, Cui W, Malarkannan S, Sodhi K, Shapiro JI, Xie Z, Sahoo D, Silverstein RL.) Circ Res. 2019 12 06;125(12):1087-1102 PMID: 31625810 PMCID: PMC6921463 SCOPUS ID: 2-s2.0-85076330129 10/19/2019
Proceedings of the Ninth HDL (High-Density Lipoprotein) Workshop: Focus on Cardiovascular Disease.

(Rodriguez A, Trigatti BL, Mineo C, Knaack D, Wilkins JT, Sahoo D, Asztalos BF, Mora S, Cuchel M, Pownall HJ, Rosales C, Bernatchez P, Ribeiro Martins da Silva A, Getz GS, Barber JL, Shearer GC, Zivkovic AM, Tietge UJF, Sacks FM, Connelly MA, Oda MN, Davidson WS, Sorci-Thomas MG, Vaisar T, Ruotolo G, Vickers KC, Martel C.) Arterioscler Thromb Vasc Biol. 2019 12;39(12):2457-2467 PMID: 31597448 PMCID: PMC6937204 SCOPUS ID: 2-s2.0-85075813183 10/11/2019
Proline residues in scavenger receptor-BI's C-terminal region support efficient cholesterol transport.

(Proudfoot SC, Sahoo D.) Biochem J. 2019 03 22;476(6):951-963 PMID: 30837308 PMCID: PMC6430181 SCOPUS ID: 2-s2.0-85063681808 03/07/2019
Liver X Receptors Suppress Activity of Cholesterol and Fatty Acid Synthesis Pathways To Oppose Gammaherpesvirus Replication.

(Lange PT, Schorl C, Sahoo D, Tarakanova VL.) mBio. 2018 07 17;9(4) PMID: 30018108 PMCID: PMC6050960 SCOPUS ID: 2-s2.0-85055540133 07/19/2018
Effect of adiposity on tissue-specific adiponectin secretion.

(Reneau J, Goldblatt M, Gould J, Kindel T, Kastenmeier A, Higgins R, Rengel LR, Schoyer K, James R, Obi B, Moosreiner A, Nicholson K, Sahoo D, Kidambi S.) PLoS One. 2018;13(6):e0198889 PMID: 29924824 PMCID: PMC6010237 SCOPUS ID: 2-s2.0-85048771061 06/21/2018
Diet-induced obesity links to ER positive breast cancer progression via LPA/PKD-1-CD36 signaling-mediated microvascular remodeling.

(Dong L, Yuan Y, Opansky C, Chen Y, Aguilera-Barrantes I, Wu S, Yuan R, Cao Q, Cheng YC, Sahoo D, Silverstein RL, Ren B.) Oncotarget. 2017 Apr 04;8(14):22550-22562 PMID: 28186980 PMCID: PMC5410244 SCOPUS ID: 2-s2.0-85016933174 02/12/2017
NMR Structure of the C-Terminal Transmembrane Domain of the HDL Receptor, SR-BI, and a Functionally Relevant Leucine Zipper Motif.

(Chadwick AC, Jensen DR, Hanson PJ, Lange PT, Proudfoot SC, Peterson FC, Volkman BF, Sahoo D.) Structure. 2017 03 07;25(3):446-457 PMID: 28162952 PMCID: PMC5575897 SCOPUS ID: 2-s2.0-85011284406 02/07/2017
Domain Mapping of Heat Shock Protein 70 Reveals That Glutamic Acid 446 and Arginine 447 Are Critical for Regulating Superoxide Dismutase 2 Function.

(Afolayan AJ, Alexander M, Holme RL, Michalkiewicz T, Rana U, Teng RJ, Zemanovic S, Sahoo D, Pritchard KA Jr, Konduri GG.) J Biol Chem. 2017 02 10;292(6):2369-2378 PMID: 28028182 PMCID: PMC5313107 SCOPUS ID: 2-s2.0-85012108909 12/29/2016
Tryptophan 415 Is Critical for the Cholesterol Transport Functions of Scavenger Receptor BI.

(Holme RL, Miller JJ, Nicholson K, Sahoo D.) Biochemistry. 2016 Jan 12;55(1):103-13 PMID: 26652912 PMCID: PMC5428993 SCOPUS ID: 2-s2.0-84954457161 12/15/2015
Impairment of Macrophage Cholesterol Efflux by Cholesterol Hydroperoxide Trafficking: Implications for Atherogenesis Under Oxidative Stress.

(Korytowski W, Wawak K, Pabisz P, Schmitt JC, Chadwick AC, Sahoo D, Girotti AW.) Arterioscler Thromb Vasc Biol. 2015 Oct;35(10):2104-13 PMID: 26315403 PMCID: PMC4601804 SCOPUS ID: 2-s2.0-84942259316 09/01/2015
Oxidized LDL-bound CD36 recruits an Na⁺/K⁺-ATPase-Lyn complex in macrophages that promotes atherosclerosis.

(Chen Y, Kennedy DJ, Ramakrishnan DP, Yang M, Huang W, Li Z, Xie Z, Chadwick AC, Sahoo D, Silverstein RL.) Sci Signal. 2015 Sep 08;8(393):ra91 PMID: 26350901 PMCID: PMC4852751 SCOPUS ID: 2-s2.0-84941034207 09/10/2015

Endocrinology and Molecular Medicine