title: Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo.
abstract: Plasma high density lipoprotein-cholesterol (HDL-C) concentrations negatively correlate with atherosclerotic cardiovascular disease. HDL is thought to have several atheroprotective functions, which are likely distinct from the epidemiological inverse relationship between HDL-C levels and risk. Specifically, strategies that reduce HDL-C while promoting reverse cholesterol transport (RCT) may have therapeutic value. The major product of the serum opacity factor (SOF) reaction versus HDL is a cholesteryl ester (CE)-rich microemulsion (CERM), which contains apo E and the CE of ~400,000 HDL particles. Huh7 hepatocytes take up CE faster when delivered as CERM than as HDL, in part via the LDL-receptor (LDLR). Here we compared the final RCT step, hepatic uptake and subsequent intracellular processing to cholesterol and bile salts for radiolabeled HDL-, CERM- and LDL-CE by Huh7 cells and in vivo in C57BL/6J mice. In Huh7 cells, uptake from LDL was greater than from CERM (2-4X) and HDL (5-10X). Halftimes for [(14)C]CE hydrolysis were 3.0±0.2, 4.4±0.6 and 5.4±0.7h respectively for HDL, CERM and LDL-CE. The fraction of sterols secreted as bile acids was ~50% by 8h for all three particles. HDL, CERM and LDL-CE metabolism in mice showed efficient plasma clearance of CERM-CE, liver uptake and metabolism, and secretion as bile acids into the gall bladder. This work supports the therapeutic potential of the SOF reaction, which diverts HDL-CE to the LDLR, thereby increasing hepatic CE uptake, and sterol disposal as bile acids.
authors.affiliation: The Laboratory of Atherosclerosis and Lipoprotein Research, Houston Methodist Research Institute, 6670 Bertner St., Houston, TX 77030, USA. Electronic address: bgillard@houstonmethodist.org.
authors.forename: Baiba K
authors.initials: BK
authors.lastname: Gillard
authors.affiliation: The Laboratory of Atherosclerosis and Lipoprotein Research, Houston Methodist Research Institute, 6670 Bertner St., Houston, TX 77030, USA. Electronic address: pjrodrig@bcm.edu.
authors.forename: Perla J
authors.initials: PJ
authors.lastname: Rodriguez
authors.affiliation: The Laboratory of Atherosclerosis and Lipoprotein Research, Houston Methodist Research Institute, 6670 Bertner St., Houston, TX 77030, USA. Electronic address: David.W.Fields@uth.tmc.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Fields
authors.affiliation: Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: jraya@bcm.edu.
authors.forename: Joe L
authors.initials: JL
authors.lastname: Raya
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: William.Lagor@bcm.edu.
authors.forename: William R
authors.initials: WR
authors.lastname: Lagor
authors.affiliation: The Laboratory of Atherosclerosis and Lipoprotein Research, Houston Methodist Research Institute, 6670 Bertner St., Houston, TX 77030, USA. Electronic address: crosales@tmhs.org.
authors.forename: Corina
authors.initials: C
authors.lastname: Rosales
authors.affiliation: University of Tennessee Health Science Center, 956 Court Avenue Room H300A, Memphis, TN 38163 USA. Electronic address: hcourtney@uthsc.edu.
authors.forename: Harry S
authors.initials: HS
authors.lastname: Courtney
authors.affiliation: The Laboratory of Atherosclerosis and Lipoprotein Research, Houston Methodist Research Institute, 6670 Bertner St., Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medical College, 1305 York Ave., New York, NY 10021, USA. Electronic address: amg2004@med.cornell.edu.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Gotto
authors.affiliation: The Laboratory of Atherosclerosis and Lipoprotein Research, Houston Methodist Research Institute, 6670 Bertner St., Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medical College, 1305 York Ave., New York, NY 10021, USA. Electronic address: HJPownall@tmhs.org.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Pownall
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D045744:Cell Line, Tumor; D002788:Cholesterol Esters / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D001647:Bile Acids and Salts; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C021908:opacity factor; D010447:Peptide Hydrolases
keywords: Bile acid secretion; Cholesterol ester metabolism; HDL function; Huh7 human hepatocytes; Reverse cholesterol transport; Serum opacity factor