Background
Cardiovascular disease (CVD) is the major cause of human mortality and morbidity in developed countries and so that identification of new therapies is an important public health priority. Dysregulated lipid metabolism leading to elevated low-density lipoprotein (LDL)-cholesterol (C) and to low plasma high-density lipoprotein (HDL)-C is an important CVD risk factor. With wider use of the statins, which lower plasma LDL-C, low HDL-C has emerged as the most important lipoprotein disorder for which current therapies are inadequate. A form of low HDL-C is associated with hypertriglyceridemia (HTG). Cases of this form are expected to rise with the epidemics of obesity-linked metabolic syndrome and diabetes, which are characterized by HTG. HDL-cholesterol and cardioprotection are mechanistically linked by reverse cholesterol transport (RCT), the transfer of cholesterol from macrophages in the subendothelial space of atherosclerotic lesion via the plasma to the liver for disposal. The major RCT steps are free cholesterol (FC) efflux from arterial macrophages, FC conversion to cholesteryl esters (CE) by plasma lecithin:cholesterol acyl transferase (LCAT), and hepatic removal of the CE by the hepatic HDL receptor SR-BI.
Hypothesis and methods
Using cryo EM, chemical kinetics, fluorescence polarization, and hydrodynamic methods, we discovered that a recombinant (r) virulence determinant from Streptococcus pyogenes , serum opacity factor (SOF), selectively delipidates human HDL by transferring the CE of ∼400,000 HDL particles to form a new particle, a CE-rich microemulsion (CERM) containing apo E, while releasing lipid-free (LF) apo A-I and a small FC- and CE-poor, “neo HDL.” SOF products have the potential for enhancing RCT. One of these, neo HDL, is half the size of HDL and is more cholesterol poor and phospholipid rich than HDL. Given that cellular cholesterol efflux and esterification are increased by increased phospholipid content of acceptors, we hypothesized that SOF-mediated conversion of HDL to neo HDL might enhance cholesterol efflux and esterification in the physiological setting of whole plasma.
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