Abstract 9012: Ablation of Neutral Cholesterol Ester Hydrolase 1 Accelerates Oxysterol-induced Macrophage Apoptosis by Aggravating Endoplasmic Reticulum Stress.
An excess of cholesterol and/or oxysterols induces apoptosis in macrophages, contributing to the development of advanced atherosclerotic lesions. In foam cells, these sterols are stored in esterified forms, which are mainly hydrolyzed by two enzymes: neutral cholesterol ester hydrolase 1 (Nceh1) and hormone-sensitive lipase (Lipe). A deficiency in either enzyme leads to accelerated growth of atherosclerotic lesions in mice. However, it is poorly understood how the esterification and hydrolysis of sterols are linked to apoptosis. While attempting to examine the intracellular structures of the Nceh1-deficient macrophages using transmission electron microscopy, we found the characteristic features of apoptosis such as condensed nuclei predominantly in Nceh1-deficient macrophages under normal culture conditions. We examined several apoptotic stimuli, and 25-hydroxycholesterol (25-HC) strikingly induced apoptosis in Nceh1-deficient macrophages (10.5% in wild-type vs 86.1% in Nceh1-deficient macrophages upon incubation with 10 μg/ml of 25-HC for 24 h). Incubation with 25-HC caused esterified 25-HC to accumulate in the endoplasmic reticulum (ER) especially in Nceh1-deficient macrophages, and the accumulation of esterified 25-HC subsequently activated ER stress signaling including the upregulation of CCAAT/enhancer-binding protein-homologous protein (CHOP, 8.8 fold increase in Nceh1-deficient macrophages), glucose-regulated protein 78 (GRP78) and increased splicing of X box binding protein 1(XBP-1). These changes leading to apoptosis were completely reversed by chemical inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) and were not observed in Lipe-deficient macrophages. The deficiency of Nceh1 also increased the number of apoptotic macrophages in atherosclerotic lesions particularly in the lipid-rich necrotic cores which contain significant amount of oxysterols. In conclusion, Nceh1 preferentially hydrolyzes oxysterol esters accumulated in the ER, thereby alleviating apoptosis preceded by ER stress. In addition to reducing the CE content of foam cells, Nceh1 may play a protective role against the progression of atherosclerosis.
- © 2010 by American Heart Association, Inc.