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

Abstract

Cellular TG stores are effi ciently hydrolyzed by adipose TG lipase (ATGL). Its coactivator comparative gene identifi cation-58 (CGI-58) strongly increases ATGLmediated TG catabolism in cell culture experiments. To investigate the consequences of CGI-58 defi ciency 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 signifi cant 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.