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Cytotoxic Effect of Triglycerides via Apoptotic Caspase Pathway in Immune and Non-immune Cell Lines
Biomed Sci Letters 2019;25:66-74
Published online March 31, 2019;  https://doi.org/10.15616/BSL.2019.25.1.66
© 2019 The Korean Society For Biomedical Laboratory Sciences.

Jaewon Lim§,*, Eun Ju Yang§,* and Jeong Hyun Chang†,*

Department of Clinical Laboratory Science, College of Medical Sciences, Daegu Haany University, Gyeongsan 38610, Korea
Correspondence to: Jeong-Hyun Chang. Department of Clinical Laboratory Science, College of Medical Science, Daegu Haany University, Gyeongsan 38610, Korea. Tel: +82-53-819-1350, Fax: +82-53-819-1353, e-mail: jhchang@dhu.ac.kr
Received January 28, 2019; Revised February 25, 2019; Accepted March 12, 2019.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract

Hyperlipidemia is defined as conditions of the accumulation of lipids such as free fatty acids (FFA), triglyceride (TG), cholesterol and/or phospholipid in the bloodstream. Hyperlipidemia can cause lipid accumulation in non-adipose tissue, which is lipid-cytotoxic effects in many tissues and mediates cell dysfunction, inflammation or programmed cell death (PCD). TG is considered to be a major cause of atherosclerosis through inflammatory necrosis of vascular endothelial cells. Recently, TG have also been shown to exhibit lipid-cytotoxicity and induce PCD. Therefore, we investigated the effect of TG on the cytotoxic effect of various cell types. When exposed to TG, the cell viability of U937 monocytes and Jurkat T lymphocytes, as well as the cell viability of MCF-7, a non-immune cell, decreased in time- and dose-dependent manner. In U937 cells and Jurkat cells, caspase-9, an intrinsic apoptotic caspase, and caspase-8, an extrinsic apoptotic caspase, were increased by exposure to TG. However, in TG-treated MCF-7 cells, caspase-8 activity increased only without caspase-9 activity. In addition, the reduction of cell viability by TG was recovered when all three cell lines were treated with pan-caspase inhibitor. These results suggest that activation of apoptotic caspases by TG causes lipotoxic effect and decreases cell viability.

Keywords : Triglyceride (TG), Lipotoxic effect, Apoptotic caspase, Caspase-8, Caspase-9
꽌 濡

怨좎삁利(hyperlipidemia) 吏냽쟻씤 怨쇱쁺뼇긽깭(overnutrition), 삉뒗 쑀쟾쟻 寃고븿(genetic defect) 벑뿉 쓽빐꽌 삁븸 궡뿉꽌 쑀由 吏諛⑹궛(free fatty acid, FFA), 以묒꽦吏諛(triglyceride, TG), 肄쒕젅뒪뀒濡(cholesterol) 삉뒗 씤吏吏(phospholipid) 媛숈 吏吏(lipid)쓽 냽룄媛 利앷맂 긽깭瑜 쓽誘명븳떎(Frayn, 2002; Kusminski et al., 2009; Johnson et al., 2013; Menet et al., 2018). 怨좎삁利앹 삁븸 궡 利앷맂 吏吏덉쓽 냽룄뿉 쓽빐 鍮 吏諛 議곗쭅(non-adipose tissue)뿉꽌 鍮꾩젙긽쟻씤 吏吏덉쓽 異뺤쟻쓣 씪쑝궎寃 릺怨 씠븣 꽭룷쓽 湲곕뒫 옣븷굹 꽭룷궗硫 벑쓣 씪쑝궎寃 릺怨 씠윭븳 쁽긽쓣 吏諛⑸룆꽦 슚怨(lipotoxic effect)씪 븳떎(Aronis et al., 2008). 씠윭븳 吏諛 異뺤쟻뿉 쓽븳 꽭룷룆꽦 슚怨쇰뒗 媛꾩꽭룷(hepatocyte), 떖洹쇱꽭룷(cardiomyocyte) 諛 떇꽭룷(macrophage) 벑 떎뼇븳 꽭룷뿉꽌 굹굹뒗 寃껋쑝濡 蹂닿퀬媛 릺怨 엳떎(de Vries et al., 1997; Aronis et al., 2005; Malhi et al., 2006). 洹몃━怨 吏諛 異뺤쟻뿉 쓽븳 꽭룷쓽 湲곕뒫 씠긽씠굹 꽭룷궗硫몄 怨좎삁利앹뿉 쓽빐 쑀諛쒕릺뒗 떎뼇븳 뿼利앹꽦 吏덊솚쓽 썝씤 以 븯굹濡 븣젮졇 엳쑝硫, 洹 以 몴쟻씤 삁媛 湲됱꽦 떖洹쇨꼍깋(acute myocardiac infarction)씠굹 뿀삁꽦 떖吏덊솚(ischemic heart disease) 벑쓽 썝씤씠 릺뒗 二쎌긽룞留κ꼍솕利(atherosclerosis)씠떎(Carmena et al., 2004).

以묒꽦吏諛⑹ 肄쒕젅뒪뀒濡ㅼ씠굹 쑀由 吏諛⑹궛怨 뜑遺덉뼱 吏諛⑸룆꽦 슚怨쇰 굹궡뒗 二쇱슂븳 씤옄 以 븯굹濡 븣젮졇 엳떎(Cury-Boaventura et al., 2006). 씠쟾쓽 뿬윭 뿰援ъ뿉꽌 二쎌긽룞留κ꼍솕利앹뿉 愿뿬븯뒗 硫댁뿭怨 꽭룷(immune cells) 以 븯굹씤 떇꽭룷쓽 寃쎌슦, 怨좎삁利 솚옄쓽 삁以 以묒꽦吏諛⑸냽룄 쑀궗븳 怨좊냽룄쓽 以묒꽦吏諛⑹뿉 끂異 떆 誘명넗肄섎뱶由ъ븘(mitochondria)쓽 湲곕뒫 씠긽 諛 솢꽦궛냼醫(reactive oxygen species, ROS) 利앷濡 씤븳 궛솕쟻 뒪듃젅뒪(oxidative stress)뿉 쓽빐 꽭룷궗硫몄쑀룄(programmed cell death, PCD)媛 씪뼱궃떎怨 蹂닿퀬븯怨 엳떎(Aronis et al., 2005; Aronis et al., 2008; Aflaki et al., 2011; Son et al., 2013; Lim et al., 2017). 洹몃━怨 以묒꽦吏諛⑹뿉 쓽븳 떇꽭룷쓽 꽭룷궗硫몄쑀룄뒗 二쎌긽룞留κ꼍솕利 諛쒕떖뿉 湲곗뿬븯硫 蹂묒쓣 씪쑝궎뒗 썝씤 以 븯굹濡 뿬寃⑥怨 엳떎(Hokanson and Austin, 1996; Malloy and Kane, 2001; Toth, 2016; Kamstrup, 2017). 寃곌낵쟻쑝濡 以묒꽦吏諛⑹뿉 쓽븳 꽭룷궗硫몄쑀룄뒗 怨좎삁利앹뿉 쓽빐 諛쒖깮 媛뒫븳 뿼利앹꽦 吏덊솚쓽 諛쒕떖 怨쇱젙뿉 以묒슂 씤옄 以 븯굹씪 븷 닔 엳쑝硫 怨좎삁利 솚옄뿉寃 諛쒖깮 媛뒫븳 吏덊솚쓽 湲곗쟾 뿰援ъ뿉 엳뼱 留ㅼ슦 以묒슂븳 遺遺꾩씠떎. 뵲씪꽌 蹂 뿰援ъ뿉꽌뒗 떇 꽭룷 쇅뿉룄 떎뼇븳 뿼利앹꽦 吏덊솚뿉 愿뿬븯뒗 硫댁뿭怨 꽭룷以 븯굹씤 U937 떒빑援 꽭룷二쇱 Jurkat T 由쇳봽援 꽭룷二, 洹몃━怨 議곌뎔쑝濡 쑀諛⑹븫 긽뵾꽭룷二쇱씤 MCF-7쓣 씠슜븯뿬 以묒꽦吏諛⑹뿉 끂異 떆 硫댁뿭怨 꽭룷 諛 鍮-硫댁뿭怨 꽭룷(non-immune cell)뿉꽌 꽭룷궗硫몄쑀룄뿉 쓽븳 꽭룷 닔 媛먯냼媛 굹굹뒗吏 솗씤븯떎.

꽭룷궗硫몄쑀룄 愿젴맂 몴쟻씤 寃쎈줈 以 븯굹씤 apoptotic caspase 湲곗쟾(apoptotic caspase pathway) caspase씪 遺덈━뒗 cysteine proteases 떒諛깆쭏 援곗쭛쓽 蹂듯빀쟻씤 솢꽦솕 諛섏쓳뿉 쓽빐 씪뼱굹怨 洹 寃곌낵, 꽭룷吏덉쓽 쓳異 諛 DNA 젅떒 諛 젅렪삎꽦쓣 珥덈옒븯硫댁꽌 꽭룷궗硫몄쓣 쑀룄븯寃 맂떎(Norbury and Hickson, 2001; Elmore, 2007). 洹몃━怨 씠 諛섏쓳뿉꽌 DNA쓽 넀긽쓣 諛⑹븯뒗 떒諛깆쭏 以 븯굹씤 poly ADP ribose polymerase (PARP)뒗 apoptotic caspase쓽 솢꽦솕뿉 쓽빐 cleaved form쓣 삎꽦븯硫 遺덊솢꽦솕릺硫댁꽌 꽭룷궗硫몄쑀룄뿉 愿뿬븯寃 릺怨 씠寃껋 씠 諛섏쓳쓽 以묒슂 湲곗쟾씠硫댁꽌 룞떆뿉 caspase 솢꽦솕뿉 쓽븳 꽭룷궗硫몄쓽 以묒슂븳 寃利 吏몴(hallmark)씠떎(Deveraux and Reed, 1999). Apoptotic caspase 湲곗쟾뿉뒗 겕寃 2醫낅쪟쓽 寃쎈줈媛 議댁옱븳떎. 泥 踰덉㎏ 寃쎈줈뒗 꽭룷 諛 닔슜泥댁뿉 쓽븳 옄洹뱀뿉 쓽빐 쑀諛쒕릺뒗 extrinsic 寃쎈줈濡 caspase 떒諛깆쭏 以 二쇰줈 caspase-8媛 愿뿬븯뒗 寃껋쑝濡 븣젮졇 엳떎. Death domain (DD)씪 遺덈━뒗 꽭룷吏 궡 domain 쇅遺쓽 옄洹뱀쓣 꽭룷 궡 떊샇쟾떖 寃쎈줈濡 쟾떖븯硫 caspase-8쓣 솢꽦솕븯寃 릺怨 씠寃껋뿉 쓽빐 꽭룷궗硫 諛섏쓳씠 쑀룄맂떎(Kischkel et al., 1995; Elmore, 2007). 몢 踰덉㎏ 寃쎈줈뒗 intrinsic 寃쎈줈씪 븯뒗뜲 洹 씠쑀뒗 꽭룷 諛 떊샇 쟾떖쓣 留ㅺ컻븯뒗 닔슜泥 옄洹뱀씠 븘땶 궡遺 옄洹뱀뿉 쓽빐 쑀룄릺湲 븣臾몄씠떎. 二쇱슂 寃쎈줈뒗 誘명넗肄섎뱶由ъ븘쓽 湲곕뒫 씠긽쑝濡 씤빐 誘명넗肄섎뱶由ъ븘 궡 cytochrome c媛 꽭룷吏 궡濡 諛⑹텧릺怨 씠寃껋뿉 쓽빐 caspase-9씠 솢꽦솕릺硫댁꽌 intrinsic 寃쎈줈媛 떆옉븯寃 맂떎(Cory and Adams, 2002; Saelens et al., 2004). 蹂 뿰援ъ뿉꽌뒗 以묒꽦吏諛⑹뿉 쓽븳 꽭룷쓽 깮議댁쑉 媛먯냼뿉 apoptotic caspase 湲곗쟾쓽 愿젴 뿬遺瑜 솗씤븯떎. 洹몃━怨 洹 湲곗쟾씠 떎젣 꽭룷쓽 깮議댁쑉怨 愿젴꽦씠 엳뒗吏 듅씠쟻 뼲젣젣瑜 씠슜븯뿬 愿젴 湲곗쟾쓣 洹쒕챸븯떎.

蹂 뿰援ъ뿉꽌뒗 以묒꽦吏諛⑹뿉 쓽븳 꽭룷궗硫몄쑀룄 怨쇱젙쓣 洹쒕챸븿뿉 엳뼱 硫댁뿭怨 꽭룷씤 U937 諛 Jurkat 꽭룷二쇱 鍮-硫댁뿭怨 꽭룷씤 MCF-7 꽭룷二쇰 씠슜빐 以묒꽦吏諛 泥섎━ 썑 꽭룷쓽 깮議댁쑉씠 뼱뼸寃 蹂솕솕뒗 吏 솗씤븯怨 떎뿕쓣 吏꾪뻾븯떎. 洹몃━怨 씠瑜 넻빐 硫댁뿭怨 꽭룷 諛 鍮-硫댁뿭怨 꽭룷뿉꽌 紐⑤몢 以묒꽦吏諛⑹뿉 쓽븳 吏諛⑸룆꽦 슚怨쇱뿉 쓽븳 꽭룷 깮議댁쑉씠 媛먯냼븯뒗 寃껋쓣 솗씤븯떎. 洹몃━怨 以묒꽦吏諛⑹뿉 쓽븳 꽭룷궗硫몄씠 apoptotic caspase瑜 寃쎌쑀븯뿬 굹굹뒗 寃껋쓣 蹂 닔 엳뿀떎.

옱猷 諛 諛⑸쾿

옱猷

以묒꽦吏諛 쑀긽븸(TG emulsion, Lipofundin® MCT/LCT 20%) B. Braun Melsungen AG (Melsungen, Germany)뿉꽌 援щℓ븯떎. 씠쟾뿉 뿬윭 뿰援ъ뿉꽌 꽭룷뿉 以묒꽦吏諛 끂異쒖떆 Lipofundin® MCT/LCT 20%쓣 궗슜븯떎. Lipofundin® MCT/LCT 20%쓽 議곗꽦 떎쓬怨 媛숇떎; 100 g/L medium chain triglyceride, soybean oil, glycerol, egg lecithin, all-rac-α-tocopherol 諛 sodium oleate. 蹂 뿰援ъ뿉꽌뒗 Lipofundin® MCT/LCT 20%쓣 씠슜븯뿬 꽭룷뿉 以묒꽦吏諛⑹쓣 끂異쒖떆耳곗쑝硫, 뵲씪꽌 以묒꽦吏諛⑹쑝濡 샎슜몴湲 븯떎(Aronis et al., 2005). Pan-caspase 뼲젣젣씤 z-VAD-FMK뒗 Sigma-Aldrich (St. Louis, MO, USA)뿉꽌 援щℓ븯떎. Western-blot 遺꾩꽍 떆 궗슜븳 cleaved caspase-8, cleaved caspase-9 諛 cleaved PARP 떒諛깆쭏뿉 븳 듅씠쟻씤 빆泥대뒗 Cell Signaling Technology (Danvers, MA, USA)뿉꽌 援щℓ 썑 궗슜븯떎.

꽭룷 諛곗뼇

U937 (ATCC, Manassas, VA, USA) 떒빑援 諛 Jurkat (ATCC) T 由쇳봽援 꽭룷二쇰뒗 10% fetal bovine serum (FBS) 諛 1% penicillin-streptomycin씠 泥④맂 RPMI 1640 諛곗뿉꽌 諛곗뼇븯떎. MCF-7 (ATCC) 쑀諛⑹븫 긽뵾꽭룷 꽭룷二쇰뒗 10% fetal bovine serum (FBS) 諛 1% penicillin-streptomycin씠 泥④맂 DMEM 諛곗뿉꽌 諛곗뼇븯떎. 諛곗뼇 議곌굔 뒿湲곌 泥④맂 5% CO2뿉꽌 37꼦瑜 쑀吏븯떎. 떎뿕 議곌굔 6-well plate뿉 2.5 × 105 cells/well 냽룄媛 릺룄濡 꽭룷瑜 떖 씠썑 以묒꽦吏諛 諛 뼲젣젣瑜 泥섎━븳 썑 24떆媛 삉뒗 48떆媛 룞븞 諛곗뼇븯떎.

꽭룷 깮議댁쑉(cell viability) 솗씤

꽭룷쓽 깮議댁쑉쓣 솗씤븯湲 쐞빐 꽭룷媛 룷븿맂 諛곗 10 μL Trypan blue 뿼깋븸 10 μL瑜 1:1 鍮꾩쑉濡 샎빀븯뒗 珥덉깮泥 뿼깋(supravital stain)쓣 떆뻾븯떎. 꽭룷 닔 媛쒖닔瑜 쐞빐 hemocytometer瑜 씠슜븯뿬 뿼깋씠 릺吏 븡 꽭룷瑜 궡븘엳뒗 꽭룷씪 媛젙븯怨 媛쒖닔븯떎.

Western-blot 遺꾩꽍

떒諛깆쭏 遺꾩꽍쓣 븯湲 쐞빐 PBS濡 꽭룷瑜 꽭泥숉븳 썑, 4꼦 議곌굔 븯뿉꽌 Triton X-100 (Sigma-Aldrich) 諛 protease inhibitor cocktail (Sigma-Aldrich)씠 룷븿맂 꽭룷 슜빐븸(cell lysis buffer)쓣 씠슜빐 꽭룷瑜 슜빐떆궓 뮘 떒諛깆쭏 긽痢듭븸쓣 뼸뼱 떎뿕뿉 씠슜븯떎. Western-blot 遺꾩꽍 씠쟾뿉 湲곗닠맂 諛붿 媛숈씠 吏꾪뻾븯떎(Lim et al., 2014).

넻怨 遺꾩꽍

넻怨 遺꾩꽍뿉뒗 GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA, USA)瑜 궗슜븯떎. P-value 媛믪 Student’s t-test瑜 궗슜븯뿬 怨꾩궛븯떎. 紐⑤뱺 媛믪 룊洹(mean) 諛 룊洹좎쓽 몴以 삤李(standard error of the mean, SEM)濡 몴떆븯떎. 媛 떎뿕 3쉶 뵫 떎뻾븯怨 媛 떎뿕 寃곌낵瑜 넗濡 넻怨꾩쟻 遺꾩꽍쓣 떎떆븯떎. 넻怨꾩쟻쑝濡 쑀쓽 븯떎怨 뙋떒릺뒗 寃곌낵뿉 빐꽑 떎쓬怨 媛숈씠 몴湲고븯떎; *P < 0.05, **P < 0.01 諛 ***P < 0.001.

寃 怨

以묒꽦吏諛⑹뿉 쓽븳 떆媛 쓽議댁쟻, 냽룄 쓽議댁쟻씤 꽭룷 닔 媛먯냼

Aronis 벑쓽 뿰援ъ뿉 뵲瑜대㈃ 以묒꽦吏諛⑹씠굹 吏諛⑹궛 벑 吏諛⑸룆꽦 슚怨쇰 굹궡硫 媛곴컖 룆由쎌쟻씤 寃쎈줈뿉 쓽빐 떇꽭룷 媛숈 硫댁뿭怨 꽭룷쓽 깮議댁쑉 媛먯냼瑜 쑀諛쒗븳떎(Aronis et al., 2008). 뵲씪꽌 蹂 뿰援ъ뿉꽌뒗 硫댁뿭怨 꽭룷二 以 떒빑援 꽭룷二쇱씤 U937 꽭룷二, T 由쇳봽援 꽭룷二쇱씤 Jurkat 꽭룷二쇰 씠슜븯뿬 以묒꽦吏諛⑹뿉 쓽븳 硫댁뿭怨 꽭룷쓽 깮議댁쑉 蹂솕瑜 愿李고븯湲 쐞븳 떎뿕쓣 吏꾪뻾븯떎. 洹몃━怨 洹 議곌뎔쑝濡 鍮-硫댁뿭怨 꽭룷二쇱씤 MCF-7 꽭룷二쇰 궗슜븯떎. 떎뿕븳 寃곌낵, 떒빑援 꽭룷二쇱씤 U937쓽 寃쎌슦 냽룄쓽 以묒꽦吏諛(0.1 mg/mL)뿉 24떆媛꾨쭔 끂異쒕릺뜑씪룄 꽭룷 깮議댁쑉씠 媛먯냼媛 슌졆븯寃 굹궗怨, 媛숈 냽룄濡 48떆媛 끂異쒕릺뿀쓣 븣 洹 닔媛 젅諛 씠븯濡 媛먯냼븯뒗 寃껋쓣 솗씤븷 닔 엳뿀떎(Fig. 1A and 1B). 諛섎㈃ T 由쇳봽援 꽭룷二쇱씤 Jurkat쓽 寃쎌슦 以묒꽦吏諛⑹뿉 24떆媛 끂異 떆뿉뒗 0.5 mg/mL뿉꽌 꽭룷 깮議댁쑉 媛먯냼媛 슌졆븯寃 굹굹湲 떆옉븯怨, 38떆媛 끂異 떆뿉룄 U937 꽭룷뿉 鍮꾪빐 以묒꽦吏諛⑹뿉 븳 媛먯닔꽦씠 궙寃 굹굹뒗 寃껋쓣 蹂댁뿬二쇱뿀떎(Fig. 1C and 1D). 삉븳, 議곌뎔씤 鍮-硫댁뿭怨 꽭룷二쇱씤 MCF-7쓽 寃쎌슦 삁긽怨 떎瑜닿쾶 以묒꽦吏諛⑹쓽 泥섎━ 떆媛 諛 냽룄뿉 빐 떎瑜 硫댁뿭怨 꽭룷二쇱 쑀궗븯寃 吏諛⑸룆꽦 슚怨쇰 굹궡硫 꽭룷 깮議댁쑉씠 媛먯냼븯뒗 寃껋쓣 솗씤븯떎(Fig. 1E and 1F). 蹂 떎뿕 寃곌낵뿉꽌 硫댁뿭怨 꽭룷二쇱쓽 寃쎌슦 꽭룷쓽 醫낅쪟뿉 뵲씪 以묒꽦吏諛⑹뿉 쓽븳 吏諛⑸룆꽦 슚怨쇱뿉 븳 媛먯닔꽦 떎瑜닿쾶 굹굹뒗 寃껋쓣 솗씤븯떎. 삉븳, 鍮-硫댁뿭怨 꽭룷二쇱뿉꽌룄 以묒꽦吏諛⑹뿉 븳 吏諛⑸룆꽦 슚怨쇨 굹굹뒗 寃껋쓣 솗씤븷 닔 엳뿀떎.

Fig. 1.

TG reduces cell viability in a time- and dose-dependent manner. (A) and (B) U937 monocytes were incubated with TG (0, 0.1, 0.2, 0.5, 1, and 2 mg/mL) for indicates times (24 and 48 h). (C) and (D) Jurkat T lymphocytes were incubated with TG (0, 0.1, 0.2, 0.5, 1, and 2 mg/mL) for indicates times (24 and 48 h). (E) and (F) MCF-7 epithelial cells were incubated with TG (0, 0.1, 0.2, 0.5, 1, and 2 mg/mL) for indicates times (24 and 48 h). The trypan blue exclusion assay was performed to detect the cell viability of cell lines. The cell viability (%) of cells without TG treatment was set as 100. Data are expressed as the mean ± SEM from three independent experiments. P-values were determined by the Student’s t-test. *P < 0.05, **P < 0.01 and ***P < 0.001.


以묒꽦吏諛⑹뿉 쓽븳 apoptotic caspase 寃쎈줈쓽 솢꽦 利앷 cleaved PARP쓽 利앷

以묒꽦吏諛⑹쓽 꽭룷 궡 異뺤쟻 떇꽭룷쓽 꽭룷궗硫몄쓣 珥덈옒븯怨, 꽭룷궗硫 寃쎈줈 以 븯굹濡 apoptotic caspase 寃쎈줈媛 븣젮졇 엳떎(Aflaki et al., 2011; Lim et al., 2017). 븵꽑 寃곌낵뿉꽌 以묒꽦吏諛⑹뿉 쓽븳 꽭룷 깮議댁쑉 媛먯냼뿉 apoptotic caspase 以 intrinsic pathway 愿젴븳 caspase-9怨 extrinsic pathway 愿젴븳 caspase-8씠 愿뿬븯뒗吏 솗씤븯湲 쐞빐 Western-blot 湲곕쾿쓣 씠슜븯뿬 솗씤븯떎. 洹 寃곌낵, U937 꽭룷二쇱 Jurkat 꽭룷二쇱뿉꽌 紐⑤몢 以묒꽦吏諛 泥섎━ 떆 caspase-8怨 caspase-9쓽 솢꽦솕뿉 쓽빐 cleaved-form씠 利앷븯뒗 寃껋쓣 솗씤븯떎(Fig. 2A and 2B). 諛섎㈃, MCF-7 꽭룷二쇱쓽 寃쎌슦 以묒꽦吏諛 泥섎━ 떆 caspase-8쓽 솢꽦룄留 利앷븯뒗 寃껋쓣 솗씤븯떎. Caspase-9쓽 cleaved-form쓽 寃쎌슦 Western-blot 긽뿉꽌 굹굹吏 븡븯떎(Fig. 2C). 꽭룷 궡 apoptotic caspase 湲곗쟾 솢꽦 떆 遺덊솢꽦솕 릺뼱 apoptosis뿉 湲곗뿬븯뒗 PARP 떒諛깆쭏쓽 蹂솕瑜 솗씤븳 寃곌낵, 紐⑤뱺 꽭룷二쇱뿉꽌 cleaved form쓽 利앷濡 씤빐 遺덊솢꽦솕 릺뒗 寃껋쓣 솗씤븯떎(Fig. 2A, 2B and 2C). 蹂 떎뿕 寃곌낵瑜 諛뷀깢쑝濡 硫댁뿭怨 꽭룷二쇱 鍮-硫댁뿭怨 꽭룷二 紐⑤몢 以묒꽦吏諛⑹뿉 끂異 떆 apoptotic caspase 湲곗쟾쓽 솢꽦솕뿉 쓽븳 PARP 떒諛깆쭏쓽 遺덊솢꽦솕媛 씪뼱굹뒗 寃껋쓣 솗씤븷 닔 엳뿀떎. 洹몃윭굹 U937怨 Jurkat 꽭룷二쇰뒗 以묒꽦吏諛⑹뿉 끂異 떆, caspase-8怨 caspase-9쓽 솢꽦씠 紐⑤몢 利앷븳 諛섎㈃ MCF-7 꽭룷二쇰뒗 caspase-8쓽 솢꽦留 利앷븯뒗 寃껋쓣 솗씤븯떎.

Fig. 2.

TG induced the activation of apoptotic caspase pathway. (A) U937 monocytes were incubated with TG (0, 0.1 and 0.2 mg/ mL) for indicates times (24 and 48 h). (B) Jurkat T lymphocytes were incubated with TG (0, 0.2 and 0.5 mg/mL) for indicates times (24 and 48 h). (C) MCF-7 epithelial cells were incubated with TG (0, 0.2 and 0.5 mg/mL) for indicates times (24 and 48 h). Cleavage of caspase-8, caspase-9 and PARP was detected by Western-blot analysis using anti-caspase-8 antibody, anti-caspase-9 antibody and anti-PARP antibody. A representative image is shown from three independent experiments.


以묒꽦吏諛⑹뿉 쓽빐 솢꽦솕맂 apoptotic caspase 湲곗쟾쓣 넻븳 꽭룷 깮議댁쑉 媛먯냼

븵꽑 寃곌낵뿉꽌 以묒꽦吏諛⑹뿉 끂異 떆 硫댁뿭怨 꽭룷 諛 鍮-硫댁뿭怨 꽭룷 紐⑤몢 꽭룷 깮議댁쑉쓽 媛먯냼媛 굹굹硫, 룞떆뿉 caspase-8 삉뒗 caspase-9쓽 솢꽦룄 利앷 PARP 떒諛깆쭏쓽 遺덊솢꽦솕媛 굹굹뒗 寃껋쓣 솗씤븯떎. 뵲씪꽌 꽭룷쓽 깮議댁쑉 媛먯냼媛 apoptotic caspase쓽 솢꽦怨 吏곸젒쟻쑝濡 뿰愿씠 엳뒗吏 솗씤븯湲 쐞븳 떎뿕쓣 吏꾪뻾븯떎. 癒쇱 以묒꽦吏諛⑹뿉 쓽븳 caspase-8 삉뒗 caspase-9쓽 솢꽦 利앷 PARP 떒諛깆쭏쓽 遺덊솢꽦솕媛 愿젴씠 엳뒗吏 솗씤븯湲 쐞븯뿬 pan-caspase 뼲젣젣씤 z-VAD-fmk瑜 媛 꽭룷二쇱뿉 냽룄蹂꾨줈 泥섎━븳 썑 PARP 떒諛깆쭏쓽 cleaved form쓽 뼇긽쓣 愿李고븳 寃곌낵, U937 꽭룷二 諛 Jurkat 꽭룷二쇱뿉꽌 紐⑤몢 PARP 떒諛깆쭏쓽 cleaved form씠 떎떆 媛먯냼븯硫댁꽌 쉶蹂듬릺뒗 寃껋쓣 愿李고븯떎(Fig. 3A and 3B). 諛섎㈃ MCF-7 꽭룷二쇱쓽 寃쎌슦 硫댁뿭怨 꽭룷二쇱 쑀궗븯寃 PARP 떒諛깆쭏씠 쉶蹂듬릺뒗 寃껋 愿李곕릺뿀쑝굹 洹 뼇긽 醫뜑 뜑뵒寃 굹굹뒗 寃껋쓣 솗씤븯떎(Fig. 3C). 씠뼱꽌 꽭룷二 蹂 꽭룷 깮議댁쑉쓣 솗씤븳 寃곌낵, 꽭 꽭룷二 紐⑤몢 caspase 솢꽦 뼲젣 떆 以묒꽦吏諛⑹뿉 쓽빐 媛먯냼븳 꽭룷 깮議댁쑉씠 씪遺 쉶蹂듬릺뒗 뼇긽쓣 굹깉떎. 以묒꽦吏諛⑹뿉 븳 媛먯닔꽦씠 넂 U937쓽 寃쎌슦뿉뒗 z-VADfmk瑜 10 μM 泥섎━ 떆 꽭룷 깮議댁쑉씠 議곌뎔 鍮 룊洹 83.9%源뚯 쉶蹂듭씠 릺뿀쑝굹, Jurkat 꽭룷二쇰뒗 룊洹 72.3%쓽 꽭룷 깮議댁쑉쓣 蹂댁뿬 10% 젙룄 李⑥씠媛 굹궗떎(Fig. 4A and 4B). 諛섎㈃, 鍮-硫댁뿭怨 꽭룷二쇱씤 MCF-7쓽 寃쎌슦 꽭룷깮議댁쑉 씪遺 쉶蹂듭씠 릺굹 洹 젙룄뒗 硫댁뿭怨 꽭룷二쇱뿉 鍮꾪빐 떎냼 궙寃 굹굹뒗 寃껋쓣 蹂댁떎(Fig. 4C). 蹂 寃곌낵瑜 諛뷀깢쑝濡 以묒꽦吏諛⑹뿉 쓽븳 끂異 떆 굹굹뒗 꽭룷쓽 깮議댁쑉 媛먯냼 湲곗쟾뿉뒗 apoptotic caspase 以 븯굹씤 caspase-8 삉뒗 caspase-9씠 愿뿬瑜 븯寃 맂떎뒗 寃껋쓣 솗씤븷 닔 엳뿀떎.

Fig. 3.

TG increases the PARP-cleaved form via caspase-8 and caspase-9. (A) U937 monocytes were incubated with 0.1 mg/mL of TG in the presence of the pan-caspase inhibitor, z-VAD-FMK (0, 2.5, 5 and 10 μM) for 48 h. (B) Jurkat T lymphocytes were incubated with 0.2 mg/mL of TG in the presence of the pan-caspase inhibitor, z-VAD-FMK (0, 2.5, 5 and 10 μM) for 48 h. (C) MCF-7 epithelial cells were incubated with 0.2 mg/mL of TG in the presence of the pan-caspase inhibitor, z-VAD-FMK (0, 2.5, 5 and 10 μM) for 48 h. Cleavage of PARP was detected by Western-blot analysis using anti-PARP antibody. β-actin was used as an internal control. A representative image is shown from three independent experiments.


Fig. 4.

TG reduces cell viability via apoptotic caspase pathway. (A) U937 monocytes were incubated with 0.1 mg/mL of TG in the presence of the pan-caspase inhibitor, z-VAD-FMK (0, 2.5, 5 and 10 μM) for 48 h. (B) Jurkat T lymphocytes were incubated with 0.2 mg/mL of TG in the presence of the pan-caspase inhibitor, z-VAD-FMK (0, 2.5, 5 and 10 μM) for 48 h. (C) MCF-7 epithelial cells were incubated with 0.2 mg/mL of TG in the presence of the pan-caspase inhibitor, z-VAD-FMK (0, 2.5, 5 and 10 μM) for 48 h. The trypan blue exclusion assay was performed to detect the cell viability of cell lines. The cell viability (%) of cells without TG treatment was set as 100. Data are expressed as the mean ± SEM from three independent experiments. P-values were determined by the Student’s t-test. *P < 0.05.


怨 李

蹂 뿰援ъ뿉꽌뒗 以묒꽦吏諛⑹씠 꽭룷뿉 끂異 떆 굹굹뒗 吏諛⑸룆꽦 슚怨쇱뿉 븳 룊媛 뜑遺덉뼱 吏諛⑸룆꽦 슚怨쇱뿉 뼱뼚븳 湲곗쟾씠 愿뿬븯뒗吏 솗씤븯떎. 湲곗〈쓽 뿰援 寃곌낵뿉꽌뒗 以묒꽦吏諛⑹뿉 쓽븳 꽭룷룆꽦 슚怨쇱 愿젴 湲곗쟾뿉 빐 二쇰줈 뿼利 吏덊솚뿉 珥덉젏쓣 留욎텛뼱 떇꽭룷, 떒빑援 삉뒗 T 由쇳봽援 벑 硫댁뿭怨 꽭룷뿉 븳 뿰援ш 二쇰 씠猷⑥뿀떎(Son et al., 2013; Toth, 2016). 洹몃윭굹 蹂 뿰援ъ뿉꽌뒗 硫댁뿭怨 꽭룷씤 U937 떒빑援ъ Jurkat T 由쇳봽援 쇅뿉룄 鍮-硫댁뿭怨 꽭룷씤 MCF-7 쑀諛⑹븫 긽뵾꽭룷뿉꽌룄 쑀궗븳 吏諛⑸룆꽦 슚怨쇨 굹굹뒗 寃껋쓣 솗씤븷 닔 엳뿀떎. 삉븳 以묒꽦吏諛⑹뿉 쓽븳 吏諛⑸룆꽦 슚怨쇱뿉 엳뼱 apoptotic caspase 寃쎈줈媛 떒빑援щ굹 떇꽭룷뿉 愿뿬븯뒗 寃껋쓣 솗씤븳 뿰援щ뒗 엳뿀쑝굹, T 由쇳봽援 諛 鍮-硫댁뿭怨 꽭룷뿉꽌 caspase-9 삉뒗 caspase-8씠 愿뿬븯뒗 寃껋 蹂 뿰援щ 넻빐 깉濡寃 諛앺옄 닔 엳뿀떎.

以묒꽦吏諛⑷낵 吏諛⑸룆꽦 슚怨쇱쓽 뿰愿꽦 겕寃 몢 媛吏 痢〓㈃뿉꽌 떎猷⑥뼱吏怨 엳떎. 泥 踰덉㎏뒗 怨좎삁利앷낵 愿젴븯뿬 꽭룷 諛뽰뿉꽌 以묒꽦吏諛⑹뿉 쓽븳 옄洹뱀씠 엳뒗 寃쎌슦뿉 굹굹뒗 꽭룷 궗硫 諛 뿼利 諛섏쓳 利앷 愿젴맂 뿰援ъ씠떎(Cury-Boaventura et al., 2006; Aronis et al., 2008; Lim et al., 2017). 몢 踰덉㎏뒗 吏諛⑸룆꽦쓣 씪쑝궎뒗 씤옄 以 븯굹씤 뙏誘명듃궛(palmitic acid)怨 媛숈 吏諛⑹궛뿉 꽭룷媛 끂異쒕릺뿀쓣 븣 꽭룷 궡뿉꽌 吏諛⑹궛쓣 以묒꽦吏諛⑹쑝濡 쟾솚븯뿬 吏諛⑸룆꽦쑝濡쒕꽣 꽭룷瑜 蹂댄샇븯뒗 寃껉낵 愿젴븳 遺遺꾩씠떎. 씠 寃쎌슦 吏吏덈궗 諛젒븳 愿젴씠 엳뒗 peroxisome proliferatoractivated receptor-γ (PPAR-γ) acyl-CoA synthetase (ASCL1)씠 솢꽦솕릺뼱 以묒꽦吏諛⑹쓽 꽭룷 궡 빀꽦쓣 珥됱쭊븯寃 릺怨 洹 寃곌낵, 꽭룷吏 궡 以묒꽦吏諛 怨쇰┰(TG droplet)씠 利앷븯뒗 寃껋쓣 蹂 닔 엳떎(Listenberger et al., 2003; Bosma et al., 2014). 蹂 뿰援 寃곌낵뿉꽌뒗 怨좎삁利앹뿉 쓽븳 以묒꽦吏諛⑹쓽 슚怨쇰 愿李고븯湲 쐞빐 꽭룷 諛뽰뿉 以묒꽦吏諛⑹쓣 泥섎━븯怨 洹 寃곌낵, 硫댁뿭怨 諛 鍮-硫댁뿭怨 꽭룷뿉꽌 紐⑤몢 apoptotic caspase쓽 솢꽦솕뿉 쓽븳 吏諛⑸룆꽦 슚怨쇰 愿李고븷 닔 엳뿀떎. 蹂 뿰援щ 룷븿븳 뿬윭 뿰援ъ뿉꽌 꽭룷吏 궡 빀꽦 利앷뿉 쓽빐 삎꽦맂 以묒꽦吏諛⑹뿉 쓽빐꽌뒗 吏諛⑸룆꽦 슚怨쇨 옒 굹굹吏 븡쑝硫 꽭룷 諛뽰뿉꽌 以묒꽦吏諛⑹뿉 쓽븳 옄洹뱀뿉 쓽빐 吏諛⑸룆꽦 슚怨쇨 利앷븯뒗 寃껋쓣 蹂댁븯쓣 븣, 以묒꽦吏諛⑹씠 꽭룷 諛 닔슜泥 삉뒗 꽭룷留됱뿉 쁺뼢쓣 二쇱뼱 굹굹뒗 寃껋쑝濡 삁긽맂떎. 洹몃윭굹 씠寃껋쓣 솗씤븯湲 쐞빐꽌뒗 異붽쟻씤 뿰援ш 뜑 븘슂븯떎.

硫댁뿭怨 꽭룷씤 떒빑援 諛 T 由쇳봽援ъ쓽 吏諛⑸룆꽦 슚怨쇰뒗 怨좎삁利 솚옄뿉꽌 굹굹뒗 뿼利앹꽦 吏덊솚 以 븯굹씤 二쎌긽룞留κ꼍솕 諛쒕떖怨 留ㅼ슦 諛젒븳 愿젴꽦씠 엳떎. 二쎌긽룞留κ꼍솕 珥덇린 蹂묐 遺쐞뿉꽌뒗 떇꽭룷굹 떒빑援, T 由쇳봽援щ 룷븿븯뒗 硫댁뿭怨 꽭룷쓽 꽭룷궗硫 諛섏쓳씠 굹굹寃 맂떎(Kolodgie et al., 2000; Feng et al., 2003). 洹몃━怨 씠寃껋 蹂묐 遺쐞쓽 二쎌긽寃쏀솕諛(atherogenic plaque)쓣 遺덉븞젙븯寃 留뚮뱾寃 릺硫 뿬윭 옄洹뱀뿉 쓽빐 遺덉븞젙빐吏 二쎌긽寃쏀솕諛섏쓣 몮윭뙎怨 엳뒗 꽟쑀吏 罹(fibrous cap)씠 뙆愿대릺硫 삁븸 쓳怨좎뿉 쓽븳 삁쟾利(thrombosis) 삎꽦뿉 쓽빐 援냼쟻씤 議곗쭅넀긽留 븘땲씪 떖븳 寃쎌슦 떖젙吏뿉 쓽븳 궗留앷퉴吏 룄떖븷 닔 엳떎(Aronis et al., 2008). 蹂 뿰援ъ뿉꽌 以묒꽦吏諛⑹뿉 끂異쒕맂 U937 떒빑援 꽭룷二 諛 Jurkat T 由쇳봽援 꽭룷二쇱쓽 꽭룷궗硫몄쑀룄 諛섏쓳쓽 利앷뒗 以묒꽦吏諛⑹씠 떒빑援 諛 T 由쇳봽援щ 넻빐 蹂묐 遺쐞쓽 諛쒕떖뿉 愿뿬븷 媛뒫꽦씠 엳쓬쓣 蹂댁뿬二쇨퀬 엳떎.

뿬윭 뿰援ъ뿉꽌 吏諛⑸룆꽦 諛섏쓳뿉 쓽븳 꽭룷궗硫몄쑀룄뒗 꽭룷 쇅遺쓽 옄洹뱀씠굹 꽭룷 궡遺뿉꽌 쑀룄릺뒗 옄洹뱀뿉 쓽빐 쑀諛쒕맆 닔 엳쓬쓣 蹂댁뿬二쇨퀬 엳떎. Aronis 벑쓽 뿰援 寃곌낵뿉 뵲瑜대㈃ 以묒꽦吏諛⑹뿉 끂異쒕맂 떇꽭룷 삉뒗 T 由쇳봽援 벑 硫댁뿭怨 꽭룷 궡뿉꽌 솢꽦궛냼醫낆씠 利앷븯寃 릺怨 씠濡 씤빐 誘명넗肄섎뱶由ъ븘쓽 湲곕뒫 씠긽씠 굹굹뒗 寃껋쓣 蹂 닔 엳떎(Aronis et al., 2005; Fernanda Cury-Boaventura et al., 2006). 洹몃━怨 씠윭븳 誘명넗肄섎뱶由ъ븘쓽 湲곕뒫 씠긽 cytochrome c뿉 쓽븳 caspase-9쓽 솢꽦솕瑜 쑀諛쒗븯뿬 intrinsic apoptotic 湲곗쟾쓽 솢꽦솕瑜 넻븳 꽭룷궗硫몄쓣 쑀룄븯寃 맂떎. 蹂 뿰援ъ뿉꽌 떎젣濡 以묒꽦吏諛⑹뿉 끂異 떆 硫댁뿭怨 꽭룷씤 U937怨 Jurkat 꽭룷二쇱뿉꽌 紐⑤몢 caspase-9쓽 cleaved form쓽 利앷瑜 솗씤븯떎. 뵲씪꽌 硫댁뿭怨 꽭룷뿉꽌 以묒꽦吏諛 끂異 떆 꽭룷궗硫몄쓽 利앷뒗 誘명넗肄섎뱶由ъ븘쓽 湲곕뒫 씠긽怨 씠濡 씤븳 caspase-9쓽 솢꽦솕媛 愿뿬븷 媛뒫꽦씠 넂떎. 洹몃━怨 caspase-9쓽 솢꽦솕濡 씤빐 굹굹뒗 PARP 떒諛깆쭏쓽 遺덊솢꽦솕뒗 caspase-3 삉뒗 caspase-7 떒諛깆쭏쓣 寃쎌쑀븯寃 릺뒗뜲 씠쟾 뿰援ъ뿉꽌 떇꽭룷뿉꽌 以묒꽦吏諛⑹뿉 쓽븳 꽭룷궗硫몄쑀룄 떆 caspase-3 諛 caspase-7쓽 솢꽦솕媛 굹굹뒗 寃껋쓣 씠誘 솗씤븳 諛 엳떎(Aronis et al., 2008; Lim et al., 2017). 뵲씪꽌 떒빑援 諛 T 由쇳봽援 삉븳 쑀궗븳 寃쎈줈瑜 怨듭쑀븷 媛뒫꽦씠 엳떎. 뵲씪꽌 씠 愿젴븳 뿰援щ 뜑 吏꾪뻾븷 븘슂꽦씠 엳떎.

쇅遺 옄洹뱀뿉 쓽븳 apoptotic caspase 湲곗쟾쓽 솢꽦뿉뒗 쇅遺뿉꽌 옄洹뱀쓣 쟾떖븯뒗 臾쇱쭏怨 洹 옄洹뱀쓣 닔슜븯뒗 꽭룷留 궡 닔슜泥닿 以묒슂븯寃 愿뿬븯寃 맂떎. 洹몃━怨 洹 옄洹뱀쓣 넻빐 꽭룷 궡 떊샇 쟾떖씠 씪뼱굹寃 릺硫 二쇰줈 caspase-8씠 솢꽦솕릺硫댁꽌 븯쐞 湲곗쟾뿉 議댁옱븯뒗 PARP 떒諛깆쭏쓣 遺덊솢꽦솕 떆耳 꽭룷궗硫몄쓣 쑀룄븯寃 맂떎. 씠윭븳 쇅遺 옄洹뱀쓣 쟾떖븯뒗 臾쇱쭏 以 몴쟻씤 떒諛깆쭏씠 tumor necrosis factor-α (TNF-α)씠떎. 씠쟾 뿰援ъ뿉꽌 T 由쇳봽援 꽭룷二쇱씤 Jurkat 꽭룷二쇱뿉 以묒꽦吏諛 泥섎━ 떆 泥섎━ 썑 24떆媛 씠궡뿉 TNF-α쓽 mRNA 諛쒗쁽웾씠 2諛 씠긽 利앷븯뒗 寃껋쓣 솗씤븯떎. 洹몃━怨 TNF-α뿉 븳 닔슜泥댁씤 TNF-αR 삉븳 洹 諛쒗쁽웾씠 2諛 씠긽 利앷븯떎. 뵲씪꽌 蹂 뿰援ъ뿉꽌 떒빑援 꽭룷二쇱씤 U937怨 T 由쇳봽援 꽭룷二쇱씤 Jurkat 꽭룷뿉꽌쓽 caspase-8쓽 솢꽦솕뿉 TNF-α뿉 쓽븳 쇅遺 옄洹뱀씠 愿뿬맆 媛뒫꽦씠 엳떎. 븳 媛吏 듅씠븳 젏 鍮꾨㈃뿭怨 꽭룷씤 MCF-7 꽭룷二 삉븳 caspase-8쓽 솢꽦씠 愿李곕맂떎뒗 젏씠떎. 洹몃━怨 硫댁뿭怨 꽭룷二쇱뒗 떎瑜닿쾶 caspase-9쓽 솢꽦 利앷뒗 굹굹吏 븡븯떎. 삉븳 pan-caspase 뼲젣젣 泥섎━ 떆 꽭룷 깮議댁쑉씠 쉶蹂듬릺뒗 寃껋쓣 蹂댁븯쓣 븣 以묒꽦吏諛⑹뿉 쓽븳 caspase-8쓽 솢꽦솕媛 吏곸젒쟻쑝濡 꽭룷궗硫 쑀룄뿉 愿뿬븿쓣 븣 닔 엳뿀떎. 뵲씪꽌 떎瑜 鍮꾨㈃뿭怨 꽭룷二쇰 솗蹂댄븯뿬 떎瑜 꽭룷二쇱뿉꽌룄 以묒꽦吏諛⑹뿉 쓽븳 꽭룷궗硫몄쑀룄뿉 caspase-8씠 愿뿬븯뒗吏 솗씤븷 븘슂꽦씠 엳떎.

蹂 뿰援ъ뿉꽌뒗 怨좎삁利앹쓣 珥덈옒븯뒗 썝씤 以 븯굹씤 以묒꽦吏諛⑹뿉 쓽븳 吏諛⑸룆꽦 슚怨쇨 硫댁뿭怨 꽭룷 諛 鍮꾨㈃뿭怨 꽭룷뿉 뼱뼸寃 쁺뼢쓣 誘몄튂뒗吏 솗씤쓣 븯怨좎옄 븯떎. 洹 寃곌낵, 硫댁뿭怨 꽭룷留 븘땲씪 鍮꾨㈃뿭怨 꽭룷뿉 紐⑤몢 吏諛⑸룆꽦 슚怨쇰 굹궡뒗 寃껋쓣 솗씤븷 닔 엳뿀怨 뜑遺덉뼱 꽭룷 닔 媛먯냼 떆 caspase-8 삉뒗 caspase-9쓣 寃쎌쑀븯뒗 apoptotic caspase 湲곗쟾씠 愿뿬븿쓣 諛앺옄 닔 엳뿀떎. 蹂 뿰援щ 諛뷀깢쑝濡 뼢썑 怨좎삁利앷낵 愿젴맂 뿰援ъ뿉 湲곗큹쟻씤 옄猷뚮 젣怨듯븷 肉 븘땲씪 移섎즺젣 媛쒕컻뿉 엳뼱 몴쟻 썑蹂대 젣怨듯븷 닔 엳쓣 寃껋쑝濡 湲곕븳떎.

ACKNOWLEDGEMENT

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2017R1C1B5076998).

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

Acknowledgments
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2017R1C1B5076998).
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