Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

Abstract

Atherosclerotic cardiovascular diseases are the leading cause of mortality in industrialized countries, despite advances in the management of coronary risk factors. Heart attacks arise from the thrombotic occlusion of coronary arteries following the rupture of plaques. Characteristic of these rupture-prone plaques is their lipid-rich nature due to the presence of cholesteryl ester (CE)-laden macrophage foam cells ( 1 ).The hydrolysis of intracellular CE, the initial step of reverse cholesterol transport, is catalyzed by multiple enzymes: neutral cholesterol ester hydrolase 1 (NCEH1) ( 2 ), also known as KIAA1363 or arylacetamide deacetylase-like 1 (AADACL1) ( 3 ), hormone-sensitive lipase (LIPE) ( 4 ), and possibly carboxylesterase 1 (CES1) ( 5, 6 ). NCEH1 is a microsomal protein tethered to the endoplasmic reticulum (ER) membrane by its N terminus with the rest of the protein containing the catalytic domain residing in the ER Abbreviations: acLDL, acetyl-LDL; Bip, immunoglobulin heavy chain-binding protein; CE, cholesteryl ester; CHOP, CCAAT/enhancer-binding protein-homologous protein; ER, endoplasmic reticulum; 25-HC, 25-hydroxycholesterol; 27-HC, 27-hydroxycholesterol; Hmgcs1 , 3-hydroxy-3-methylglutaryl-CoA synthase 1; 7-KC, 7-ketocholesterol; LD, lipid droplet; LIPE, hormone-sensitive lipase; LPDS, lipoprotein defi cient serum; LXR, liver X receptor; NCEH1, neutral cholesterol ester hydrolase 1; PPPA, pyripyropene A; Srebp, sterol regulatory element binding protein; TEM, transmission electron microscopy; TGEM, thioglycollate-elicited peritoneal macrophage; TUNEL, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; Xbp-1, X-box-binding protein 1 . This work was supported by a grant-in-aid from Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists, a grant-in-aid for Scientifi c Research from the Ministry of Education and Science, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and JKA through its promotion funds from KEIRIN RACE, and MEXT-Supported Program for the Strategic Research

3‐Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines

“…Because of the effects of the schweinfurthin compounds on FPP and GGPP and our earlier observation that they induce a form of ER stress [22], our hypothesis was that the schweinfurthins could more globally alter isoprenoid pathway metabolites and cholesterol homeostasis in a manner reminiscent of oxysterol 25-hydroxycholesterol [23]. Herein, we describe the effects of 3dSB on cholesterol content and cholesterol synthesis in cell lines with varying sensitivity to the antiproliferative effects of the schweinfurthins.…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…ERS-induced apoptosis in macrophages may be due to neutral cholesterol ester hydrolase 1 (Nceh1). Sekiya et al [86] reported that Nceh1-deficient thioglycollate-elicited peritoneal macrophages (TGEMs) were susceptible to apoptosis induced by oxysterols, particularly 25-hydroxycholesterol (25-HC). Incubation with 25-HC caused massive accumulation of 25-HC ester in the ER due to its defective hydrolysis function, thereby activating ERS signaling proteins such as CHOP.…”

Dietary compound α‐asarone alleviates ER stress‐mediated apoptosis in 7β‐hydroxycholesterol‐challenged macrophages

“…It has been shown that cytotoxic oxysterols induced apoptosis via enhancing ER stress . 7β‐Hydroxycholesterol activated IRE1α by phosphorylation, an ER transmembrane sensor that activates the UPR to maintain the ER and cellular function.…”