Streptococcal Serum Opacity Factor Increases the Rate of Hepatocyte Uptake of Human Plasma High-Density Lipoprotein Cholesterol

摘要

Serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes, converts plasmanhigh-density lipoproteins (HDL) to three distinct species: lipid-free apolipoprotein (apo) A-I, neo HDL, ansmall discoidalHDL-like particle, and a large cholesteryl ester-richmicroemulsion (CERM) that contains thencholesterol esters (CE) of up to ∼400000 HDL particles and apo E as its major protein. Similar SOF reactionnproducts are obtained withHDL, total plasma lipoproteins, and whole plasma.We hypothesized that hepaticnuptake of CERM-CE via multiple apo E-dependent receptors would be faster than that of HDL-CE.nWe tested our hypothesis using human hepatoma cells and lipoprotein receptor-specific Chinese hamsternovary (CHO) cells. The uptake of [n3nH]CE by HepG2 and Huh7 cells from HDL after SOF treatment, whichntransfers >90% of HDL-CE to CERM, was 2.4 and 4.5 times faster, respectively, than from control HDL.nCERM-[n3nH]CE uptake was inhibited by LDL and HDL, suggestive of uptake by both the LDL receptorn(LDL-R) and scavenger receptor class B type I (SR-BI). Studies in CHO cells specifically expressing LDL-Rnand SR-BI confirmed CERM-[n3nH]CE uptake by both receptors.RAP and heparin inhibit CERM-[n3nH]CE butnnot HDL-[n3nH]CE uptake, thereby implicating LRP-1 and cell surface proteoglycans in this process. Thesendata demonstrate that SOF treatment of HDL increases the rate of CE uptake via multiple hepatic apo Enreceptors. In so doing, SOF might increase the level of hepatic disposal of plasma cholesterol in a way that isntherapeutically useful