Deletion of CGI-58 or adipose triglyceride lipase differently affects macrophage function and atherosclerosis

被引：25

作者：

Goeritzer, Madeleine ^{[1
]}

Schlager, Stefanie ^{[1
]}

Radovic, Branislav ^{[1
]}

Madreiter, Corina T. ^{[1
]}

Rainer, Silvia ^{[1
]}

Thomas, Gwynneth ^{[3
]}

Lord, Caleb C. ^{[4
]}

Sacks, Jessica ^{[5
]}

Brown, Amanda L. ^{[5
]}

Vujic, Nemanja ^{[1
]}

Obrowsky, Sascha ^{[1
]}

Sachdev, Vinay ^{[1
]}

Kolb, Dagmar ^{[2
]}

Chandak, Prakash G. ^{[1
]}

Graier, Wolfgang F. ^{[1
]}

Sattler, Wolfgang ^{[1
]}

Brown, J. Mark ^{[5
]}

Kratky, Dagmar ^{[1
]}

机构：

[1] Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, Graz, Austria

[2] Med Univ Graz, Ctr Med Res, Inst Cell Biol Histol & Embryol, Graz, Austria

[3] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Sect Lipid Sci, Winston Salem, NC 27103 USA

[4] Univ Texas SW Med Ctr Dallas, Div Hypothalam Res, Dallas, TX 75390 USA

[5] Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA

来源：

JOURNAL OF LIPID RESEARCH | 2014年 / 55卷 / 12期

基金：

奥地利科学基金会;

关键词：

inflammation; lipid droplets; storage diseases; comparative gene identification-58; COMPARATIVE GENE IDENTIFICATION-58; CHANARIN-DORFMAN-SYNDROME; LIPID STORAGE DISEASE; INSULIN-RESISTANCE; HEPATIC STEATOSIS; MICE; LIPOLYSIS; METABOLISM; PROTEIN; CATABOLISM;

D O I：

10.1194/jlr.M052613

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cellular TG stores are efficiently hydrolyzed by adipose TG lipase (ATGL). Its coactivator comparative gene identification-58 (CGI-58) strongly increases ATGL-mediated TG catabolism in cell culture experiments. To investigate the consequences of CGI-58 deficiency in murine macrophages, we generated mice with a targeted deletion of CGI-58 in myeloid cells (macCGI-58(-/-) mice). CGI-58(-/-) macrophages accumulate intracellular TG-rich lipid droplets and have decreased phagocytic capacity, comparable to ATGL(-/-) macrophages. In contrast to ATGL(-/-) macrophages, however, CGI-58(-/-) macrophages have intact mitochondria and show no indications of mitochondrial apoptosis and endoplasmic reticulum stress, suggesting that TG accumulation per se lacks a significant role in processes leading to mitochondrial dysfunction. Another notable difference is the fact that CGI-58(-/-) macrophages adopt an M1-like phenotype in vitro. Finally, we investigated atherosclerosis susceptibility in macCGI-58/ApoE-double KO (DKO) animals. In response to high-fat/high-cholesterol diet feeding, DKO animals showed comparable plaque formation as observed in ApoE(-/-) mice. In agreement, antisense oligonucleotide-mediated knockdown of CGI-58 in LDL receptor(-/-) mice did not alter atherosclerosis burden in the aortic root. These results suggest that macrophage function and atherosclerosis susceptibility differ fundamentally in these two animal models with disturbed TG catabolism, showing a more severe phenotype by ATGL deficiency.

引用

页码：2562 / 2575

页数：14

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