Journal of Lipid Research 2014-12-01

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

Madeleine Goeritzer, Stefanie Schlager, Branislav Radovic, Corina T Madreiter, Silvia Rainer, Gwynneth Thomas, Caleb C Lord, Jessica Sacks, Amanda L Brown, Nemanja Vujic, Sascha Obrowsky, Vinay Sachdev, Dagmar Kolb, Prakash G Chandak, Wolfgang F Graier, Wolfgang Sattler, J Mark Brown, Dagmar Kratky

Index: J. Lipid Res. 55(12) , 2562-75, (2014)

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Abstract

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. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.