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

J Lipid Res. 2014 Dec;55(12):2562-75. doi: 10.1194/jlr.M052613. Epub 2014 Oct 14.

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.

Keywords: comparative gene identification-58; inflammation; lipid droplets; storage diseases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Acylglycerol-3-Phosphate O-Acyltransferase / antagonists & inhibitors
  • 1-Acylglycerol-3-Phosphate O-Acyltransferase / genetics
  • 1-Acylglycerol-3-Phosphate O-Acyltransferase / metabolism*
  • Animals
  • Apoptosis
  • Atherosclerosis / etiology
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cells, Cultured
  • Crosses, Genetic
  • Diet, High-Fat / adverse effects
  • Female
  • Gene Deletion*
  • Gene Knockdown Techniques
  • Lipase / genetics
  • Lipase / metabolism*
  • Lipid Droplets / immunology
  • Lipid Droplets / metabolism
  • Lipid Droplets / ultrastructure
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / ultrastructure
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Oligonucleotides, Antisense / administration & dosage
  • Phagocytosis*
  • Triglycerides / metabolism

Substances

  • Oligonucleotides, Antisense
  • Triglycerides
  • 1-Acylglycerol-3-Phosphate O-Acyltransferase
  • Abhd5 protein, mouse
  • Lipase
  • PNPLA2 protein, mouse