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Daisy Sahoo, PhD investigates the role of HDL in cardiovascular disease: Preventing good cholesterol from going bad

Cardiovascular disease (CVD), encompassing coronary heart disease, hypertension and stroke, is the leading cause of death among Americans across all racial and ethnic groups. Importantly, as it accounts for 35% of all deaths in the state, CVD is the primary cause of death in Wisconsin, surpassing all cancers combined. Apart from being a major health issue, direct and indirect costs for CVD-related care is also a major economic burden on tax payers. As such, additional CVD research, prevention and awareness is absolutely required to reduce and reverse these alarming trends in our state and nation as a whole.

Plasma cholesterol is transported by low density lipoproteins (LDL, the “bad cholesterol”) and high density lipoproteins (HDL, the “good cholesterol”); the proportion of cholesterol in each particle is a strong indicator of atherosclerotic risk. While epidemiological studies support a protective role for HDL against CVD, the benefits of raising HDL levels are currently controversial. For example, genetically-modified mice that have high HDL levels are more prone to atherosclerosis. Further, recent large-scale clinical studies revealed that patients who had normal levels of HDL-cholesterol still suffered cardiovascular events. Moreover, a phase III human clinical trial recently came to an abrupt end as the pharmacological doubling of HDL levels resulted in high patient mortality. For these reasons, there is now a greater emphasis on enhancing HDL function and promoting cholesterol flux from peripheral tissues to the liver by a process called reverse cholesterol transport. Since the binding of HDL to its receptor, scavenger receptor class B type I (SR-BI), is critical during the last step of reverse cholesterol transport, SR-BI is a promising target for enhancing whole-body cholesterol removal, reducing plasma cholesterol levels and preventing CVD. As such, Daisy Sahoo, PhD, Assistant Professor in the Division of Endocrinology, Metabolism and Clinical Nutrition, and her laboratory are investigating the detailed mechanisms by which HDL interacts with SR-BI to mediate efficient cholesterol transfer to the liver. Her findings will lead to development of strategies that can promote the natural off-loading of cholesterol from circulation and prevent the formation of dysfunctional HDL (i.e. oxidized HDL) that is known to promote atherogenesis.

SR-BI is a glycosylated cell surface receptor that is highly expressed in tissues that exhibit high rates of cholesterol catabolism. The anti-atherogenic properties of SR-BI and its ability to promote cholesterol removal are firmly established in studies of genetically-modified mice. SR-BI-mediated selective uptake of HDL-cholesterol is a two-step process that involves (i) binding of HDL to the extracellular (EC) domain of SR-BI followed by (ii) transfer of esterified cholesterol to the plasma membrane. To examine the first step of selective uptake, Dr. Sahoo’s research team is currently identifying the sites of physical interaction between HDL/SR-BI receptor/ligand complexes using a powerful combination of standard biochemical/protein chemistry techniques such as site-specific photo-reactive crosslinking and mass spectrometry methodologies. Further, her lab is elucidating key molecular features of the EC domain of SR-BI that influence receptor/ligand interactions. To date, her lab has already identified key hydrophobic regions, as well as specific disulfide bonds, that influence the organization of the EC domain and, as a result, SR-BI-mediated cholesterol transport.

To examine the second step of HDL-CE selective uptake, the Sahoo laboratory is examining the physiological relevance of SR-BI oligomerization in cholesterol metabolism in vivo. Recent evidence from the Sahoo lab for the existence of SR-BI oligomers supports the notion that HDL-cholesterol uptake occurs via a non-aqueous pathway, possibly involving the formation of a “hydrophobic channel”. Dr. Sahoo has already published findings that demonstrate the occurrence of SR-BI dimerization in living cells using fluorescence resonance energy transfer (FRET). Her research team is now applying a highly innovative imaging technique that couples FRET with bimolecular fluorescence complementation to identify, for the first time, an SR-BI oligomeric complex, in live cells. With these experiments, performed in parallel with in vivo studies in mice expressing mutant SR-BI receptors, the Sahoo laboratory hopes to provide the first correlation of higher order oligomer formation with SR-BI’s lipid transfer functions.

With her long-standing interest in lipoprotein metabolism and her strong background in biochemistry, Dr. Sahoo is well-poised to apply novel, cutting-edge techniques to further our understanding of the mechanisms underlying ligand recognition and selective uptake of HDL-cholesterol. These results will promote the development of a new class of atheroprotective therapies based on strengthening the SR-BI/apoA-I interaction, enhancing HDL function and improving cholesterol disposal to reduce CVD.
 

Article written by Daisy Sahoo, PhD, Division of Endocrinology, Metabolism and Clinical Nutrition

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