Zymosan-mediated inflammation impairs in vivo reverse cholesterol transport

Abstract

or the movement of cholesterol from peripheral cells, including lipid laden macrophages, to the liver for excretion. This pathway involves multiple steps including: 1 ) the effl ux of cholesterol to lipid poor apolipoproteins and HDL; 2 ) the maturation of HDL through cholesterol esterifi cation via lethicin cholesterol acyl transferase; 3 ) the uptake of HDL cholesterol by the liver; and 4 ) hepatic cholesterol excretion into the biliary system and feces in the form of bile acids and free cholesterol ( 2, 3 ). Thus, understanding the mechanism of RCT and the pathophysiological factors affecting RCT has been a topic of immense research focus with potential clinical signifi cance.Infl ammation may be a potent source of HDL and RCT dysfunction. HDL undergoes multiple structural changes with infl ammation rendering it into "acute phase HDL", which is relatively enriched in free fatty acids, triglycerides, serum amyloid A (SAA), and apolipoprotein (apo)A-IV, whereas cholesterol esters and anti-infl ammatory enzymes including paraoxanase 1 are decreased ( 4-6 ). In addition, infl ammation induces secretion of myeloperoxidase (MPO), which has been shown to modify apoAI and impair its ability to accept cholesterol ( 7-10 ). Finally infl ammation affects gene expression in the liver, which has consequences for cholesterol uptake and excretion ( 4,11,12 ). Understanding the mechanisms behind the infl ammatory impairment of RCT is clinically relevant as chronic infl ammatory conditions such as diabetes, metabolic syndrome, and rheumatoid arthritis are prevalent in our society and associated with an increased atherosclerotic burden ( 13,14 ).Although a majority of the studies on infl ammatory impairment of RCT have been in vitro, two recent studies Abstract Infl ammation has been proposed to impair HDL function and reverse cholesterol transport (RCT). We investigated the effects of infl ammation mediated by zymosan, a yeast glucan, on multiple steps along the RCT pathway in vivo and ex vivo. Acute infl ammation with 70 mg/kg zymosan impaired RCT to plasma, liver, and feces similarly by 17-22% ( P < 0.05), with no additional block at the liver. Hepatic gene expression further demonstrated no change in ABCG5, ABCB4, and ABCB11 expression but a decline in ABCG8 mRNA (32% P < 0.05). Plasma from zymosan-treated mice had a 21% decrease in cholesterol acceptor ability ( P < 0.01) and a 35% decrease in ABCA1-specfi c effl ux capacity ( P < 0.01) in vitro. Zymosan treatment also decreased HDL levels and led to HDL remodeling with increased incorporation of serum amyloid A. In addition, cholesterol effl ux from cultured macrophages declined with zymosan treatment in a dose dependant manner. Taken together, our results suggest that zymosan impairs in vivo RCT primarily by decreasing macrophage-derived cholesterol entering the plasma, with minimal additional blocks downstream. Our study supports the notion that RCT impairment is one of the mechanisms for the increased atherosclerotic burden observed in infl ammatory conditions. -Malik...

Inhibition of soluble epoxide hydrolase in mice promotes reverse cholesterol transport and regression of atherosclerosis

“…However, the smallest increase was observed in the liver. RCT is a dynamic process and different intermediate compartments may influence liver 3 H-counts from cholesterol in opposite directions; for example, improved adipocyte cholesterol efflux increases liver 3 H-levels, whereas enhanced flux through the liver to feces may decrease them [24,36]. Thus, we speculate that the excess cholesterol present in the plasma after the drug treatment could have already been transported through the liver to the bile and feces.…”

Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice

“…Native SAA has been shown to alter both the protein and lipid composition of AP-HDL (14) and also to influence HDL remodeling (15) and cholesterol efflux from cells (16). Although several studies have reported that inflammation impedes reverse cholesterol transport to the liver (17)(18)(19), we have recently shown that impairment of reverse cholesterol transport in mice during inflammation does not depend on SAA (20). An absence of SAA also did not affect atherosclerosis in an apoE-deficient mouse model (21).…”

HDL from apoA1 transgenic mice expressing the 4WF isoform is resistant to oxidative loss of function

“…Our prior study demonstrated that cholesterol effl ux increased linearly with mouse plasma concentrations up to 0.5% ( 30 ); thus, we used 0.4% (v/v) in our effl ux studies ( 40 ). The plasma from human apoA1 and 4WF transgenic mice similarly increased cholesterol effl ux from BMDMs by 2.9-and 3.2-fold, respectively, compared with no plasma control ( Fig.…”

“…We previously demonstrated that zymosan induces an acute infl ammatory response in mice, which reduces RCT ( 40 ). Three days later, we assayed the mouse plasma for human apoA1 containing the MPO-specifi c oxTrp72 modifi cation using a newly developed sensitive and specifi c ELISA assay ( 30 ).…”