Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo

Biochim Biophys Acta. 2016 Mar;1861(3):196-204. doi: 10.1016/j.bbalip.2015.12.006. Epub 2015 Dec 18.

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.

Keywords: Bile acid secretion; Cholesterol ester metabolism; HDL function; Huh7 human hepatocytes; Reverse cholesterol transport; Serum opacity factor.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology*
  • Apolipoproteins E / metabolism
  • Bile Acids and Salts / metabolism*
  • Cell Line, Tumor
  • Cholesterol Esters / metabolism*
  • Cholesterol, HDL / metabolism
  • Cholesterol, LDL / metabolism
  • Gene Expression Regulation
  • Humans
  • Hydrolysis
  • Kinetics
  • Lipid Metabolism / drug effects*
  • Lipid Metabolism / genetics
  • Liver / drug effects*
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Peptide Hydrolases / pharmacology*

Substances

  • Anticholesteremic Agents
  • Apolipoproteins E
  • Bile Acids and Salts
  • Cholesterol Esters
  • Cholesterol, HDL
  • Cholesterol, LDL
  • opacity factor
  • Peptide Hydrolases