title: Streptococcal serum opacity factor increases the rate of hepatocyte uptake of human plasma high-density lipoprotein cholesterol.
abstract: Serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes, converts plasma high-density lipoproteins (HDL) to three distinct species: lipid-free apolipoprotein (apo) A-I, neo HDL, a small discoidal HDL-like particle, and a large cholesteryl ester-rich microemulsion (CERM) that contains the cholesterol esters (CE) of up to ∼400000 HDL particles and apo E as its major protein. Similar SOF reaction products are obtained with HDL, total plasma lipoproteins, and whole plasma. We hypothesized that hepatic uptake of CERM-CE via multiple apo E-dependent receptors would be faster than that of HDL-CE. We tested our hypothesis using human hepatoma cells and lipoprotein receptor-specific Chinese hamster ovary (CHO) cells. The uptake of [(3)H]CE by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was 2.4 and 4.5 times faster, respectively, than from control HDL. CERM-[(3)H]CE uptake was inhibited by LDL and HDL, suggestive of uptake by both the LDL receptor (LDL-R) and scavenger receptor class B type I (SR-BI). Studies in CHO cells specifically expressing LDL-R and SR-BI confirmed CERM-[(3)H]CE uptake by both receptors. RAP and heparin inhibit CERM-[(3)H]CE but not HDL-[(3)H]CE uptake, thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases the rate of CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase the level of hepatic disposal of plasma cholesterol in a way that is therapeutically useful.
authors.affiliation: Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, United States. baibag@bcm.tmc.edu
authors.forename: Baiba K
authors.initials: BK
authors.lastname: Gillard
authors.forename: Corina
authors.initials: C
authors.lastname: Rosales
authors.forename: Biju K
authors.initials: BK
authors.lastname: Pillai
authors.forename: Hu Yu
authors.initials: HY
authors.lastname: Lin
authors.forename: Harry S
authors.initials: HS
authors.lastname: Courtney
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Pownall
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000378:metabolism; D016466:CHO Cells / Q000378:metabolism; D018929:Cell Culture Techniques; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000187:drug effects / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D018613:Microscopy, Confocal; D010447:Peptide Hydrolases / Q000494:pharmacology*; D013297:Streptococcus pyogenes / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence
chemical_list: D001896:Boron Compounds; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; C021908:opacity factor; C084200:cholesteryl 4,4-difluoro-5,7-dimethyl-4-bora-3,4-diaza-3-indacenedodecanoate; D010447:Peptide Hydrolases