Abstract 326: Streptococcal Serum Opacity Factor Product, Cholesteryl Ester Rich Particles, Induce Cholesterol Ester Metabolism and Bile Acid Secretion after Uptake by Human Huh7 Hepatocytes

Plasma concentrations of HDL-cholesterol (C) negatively correlate with atherosclerotic cardiovascular disease. Nevertheless, current evidence suggests that this correlation is not axiomatic and that some forms of HDL are dysfunctional and atherogenic. Interventions that raise HDL-C have not been uniformly successful suggesting that mechanisms by which HDL-C is increased determine its anti atherogenic potency. Additionally, mice overexpressing the HDL receptor, SR-BI, have lower plasma HDL-C levels and less atherosclerosis. Thus, new strategies that reduce HDL-C while promoting reverse cholesterol transport (RCT) may have therapeutic value. Serum opacity factor (SOF) disrupts HDL and forms three products, including a cholesteryl ester-rich microemulsion (CERM) containing apo E and the CE of ~400,000 HDL particles. Hepatic CE uptake in Huh7 cells is faster when delivered by CERM than by HDL, and cleared both in vitro and in vivo, in part, via the LDL-receptor (LDLR). We investigated the therapeutic potential of SOF in promoting RCT by comparing the final RCT steps, hepatic uptake, CE metabolism to cholesterol and bile salts, and secretion, of [ 14 C]-CE-HDL, -CERM and [[Unable to Display Character: –]]LDL. Cells were pulse-labeled for 2 h with 20-50 ug/mL HDL protein (6-17 ug/mL [ 14 C]-CE), or the CE-equivalent as CERM or LDL, and chased for 0, 2 or 6 h. Cells, pulse media and chase media were analyzed for sterols by beta-counting, TLC and solvent partitioning. [ 14 C]CE 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 ± 0.7 h respectively for HDL, CERM and LDL-CE. Bile acids in cells after uptake from HDL or CERM were low, <0.2% of total sterol but higher in cells after uptake from LDL, 4.2 ± 2.2 % of total sterol ( p = 0.03 ) at the 2 h chase time. The fraction of sterols secreted as bile acids was comparable for all three donor particles. After the 2 h chase, ~40% of the secreted sterols were bile acids, and after 6 h, ~ 50% were bile acids. These ratios were the same for cells treated with 14 C-CE-HDL, CERM or LDL. Thus, the rates of hepatic metabolism of CERM-CE to free cholesterol, to bile acids and secretion are intermediate between those for HDL- and LDL-CE, supporting the therapeutic potential of SOF as a promoter of RCT.

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