Publications

• Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages.

  Crow J.A., Middleton B.L., Borazjani A., Hatfield M.J., Potter P.M., Ross M.K.

  Cholesteryl esters are hydrolyzed by cholesteryl ester hydrolase (CEH) yielding free cholesterol for export from macrophages. Hence, CEH has an important regulatory role in macrophage reverse cholesterol transport (RCT). CEH and human carboxylesterase 1 (CES1) appear to be the same enzyme. CES1 is ... >> More

  Cholesteryl esters are hydrolyzed by cholesteryl ester hydrolase (CEH) yielding free cholesterol for export from macrophages. Hence, CEH has an important regulatory role in macrophage reverse cholesterol transport (RCT). CEH and human carboxylesterase 1 (CES1) appear to be the same enzyme. CES1 is inhibited by oxons, the bioactive metabolites of organophosphate (OP) pesticides. Here, we show that CES1 protein is robustly expressed in human THP-1 monocytes/macrophages and its biochemical activity inhibited following treatment of cell lysates and intact cells with chlorpyrifos oxon, paraoxon, or methyl paraoxon (with nanomolar IC(50) values) or after immunodepletion of CES1 protein. CES1 protein expression in cells is unaffected by a 24-h paraoxon treatment, suggesting that the reduced hydrolytic activity is due to covalent inhibition of CES1 by oxons and not down-regulation of expression. Most significantly, treatment of cholesterol-loaded macrophages with either paraoxon (a non-specific CES inhibitor) or benzil (a specific CES inhibitor) caused enhanced retention of intracellular cholesteryl esters and a "foamy" phenotype, consistent with reduced cholesteryl ester mobilization. Thus, exposure to OP pesticides, which results in the inhibition of CES1, may also inhibit macrophage RCT, an important process in the regression of atherosclerosis. << Less

  Biochim. Biophys. Acta 1781:643-654(2008) [PubMed] [EuropePMC]

• Stable overexpression of human macrophage cholesteryl ester hydrolase results in enhanced free cholesterol efflux from human THP1 macrophages.

  Zhao B., Song J., St Clair R.W., Ghosh S.

  Reduction of the lipid burden of atherosclerotic lesion-associated macrophage foam cells is a logical strategy to reduce the plaque volume. Since extracellular cholesterol acceptor-mediated cholesterol efflux is the only recognized mechanism of cholesterol removal from foam cells and this process ... >> More

  Reduction of the lipid burden of atherosclerotic lesion-associated macrophage foam cells is a logical strategy to reduce the plaque volume. Since extracellular cholesterol acceptor-mediated cholesterol efflux is the only recognized mechanism of cholesterol removal from foam cells and this process is rate limited at the level of intracellular cholesterol ester hydrolysis, a reaction catalyzed by neutral cholesteryl ester hydrolase (CEH), we examined the hypothesis that CEH overexpression in the human macrophage monocyte/macrophage cell line THP1 results in increased cholesterol efflux, as well as decreased cellular cholesterol ester accumulation. We generated THP1-CEH cells with stable integration of human macrophage CEH cDNA driven by the cytomegalovirus promoter. Compared with wild-type THP1 cells (THP1-WT), THP1-CEH cells showed increased CEH mRNA expression and increased CEH activity. Efflux of free or unesterified cholesterol by acetylated LDL-loaded THP1-CEH cells to ApoA-I by an ABCA1-dependent pathway or to HDL by an ABCG1-dependent pathway was significantly higher than that in THP1-WT cells. In addition, THP1-CEH cells accumulated significantly lower amount of esterified cholesterol. CEH overexpression, therefore, not only enhances cholesterol efflux but also reduces cellular accumulation of cholesteryl esters. Taken together, these data provide evidence for evaluating CEH expression in human macrophages as a potential target for attenuation of foam cell formation and regression of atherosclerotic plaques. << Less

  Am. J. Physiol. 292:C405-C412(2007) [PubMed] [EuropePMC]