title: Chylomicron remnant model emulsions induce intracellular cholesterol accumulation and cell death due to lysosomal destabilization.
abstract: Chylomicron remnants, which carry dietary fats and cholesterol, play a role in promoting atherosclerosis. Chylomicron remnants are characterized by high cholesterol content at the surface, different from low-density lipoproteins (LDLs) containing high amounts of esterified cholesterol (CE) in the core. We prepared cholesterol-rich emulsions (TO-PC/cholesterol emulsions) as models for chylomicron remnants and compared their effects on J774 macrophages with acetylated-LDL (ac-LDL). Internalization of TO-PC/cholesterol emulsions into macrophages reduced cell viability, whereas ac-LDL did not. Surprisingly, there was no difference in intracellular free cholesterol content between cells incubated with TO-PC/cholesterol emulsions and with ac-LDL. Furthermore, cholesterol in TO-PC/cholesterol emulsions and ac-LDL both were internalized into J774 macrophages; however, incubation with TO-PC/cholesterol emulsions induced leakage of lysosomal protease, cathepsin-L, to cytosol, which was not observed for incubation with ac-LDL. Inhibition of the activity of cathepsin-L recovered the viability of macrophages that ingested TO-PC/cholesterol emulsions. We suggest an alternative fate of cholesterol-rich emulsions taken up by macrophages, which is different from other atherogenic lipoproteins rich in CE; internalization of TO-PC/cholesterol emulsions into macrophages induces rapid free cholesterol accumulation in lysosomes and cell death due to lysosomal destabilization.
authors: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Kyoko
authors: K
authors: Wakita
authors: Department of Pharmacy, Shiga University of Medical Science Hospital, Otsu, Shiga 520-2192, Japan.
authors: Shin-ya
authors: SY
authors: Morita
authors: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Naoko
authors: N
authors: Okamoto
authors: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Eriko
authors: E
authors: Takata
authors: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minami-Tamagaki-cho, Suzuka, Mie 513-8670, Japan.
authors: Tetsurou
authors: T
authors: Handa
authors: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: mnakano@pha.u-toyama.ac.jp.
authors: Minoru
authors: M
authors: Nakano
mesh_terms: D000818:Animals; D001692:Biological Transport; D016923:Cell Death; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D053298:Chylomicron Remnants / Q000378:metabolism*; D004655:Emulsions; D008077:Lipoproteins, LDL / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010713:Phosphatidylcholines / Q000378:metabolism; D014304:Triolein / Q000378:metabolism
chemical_list: D053298:Chylomicron Remnants; D004655:Emulsions; D008077:Lipoproteins, LDL; D010713:Phosphatidylcholines; C032629:acetyl-LDL; D014304:Triolein; D002784:Cholesterol
keywords: Apolipoprotein E; Cathepsin-L; J774 macrophages; ac-LDL