PPAR- dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation
Ajay Chawla1, 2, Yaacov Barak1, Laszlo Nagy4, Debbie Liao1, Peter Tontonoz3
& Ronald M. Evans1
1
The Salk Institute for Biological Studies, Howard Hughes Medical Institute, La Jolla, California 90237, USA
2
Division of Endocrinology and Metabolism, University of California, San Diego, California 92093, USA
3
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA
4
Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Nagyerdei krt. 98, Debrecen H-4012, Hungary
Correspondence should be addressed to Ronald M. Evans evans@salk.edu
Peroxisome proliferator-activated receptor- (PPAR-) is highly expressed in lipid-accumulating macrophages of the coronary artery. In light of this, the wide-spread clinical use of thiazolidinediones (TZDs) in the treatment of type II diabetes raises concerns about the role of PPAR- in macrophage function and disease progression. To define the role of PPAR- in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR- gene. We demonstrate here that PPAR- is neither essential for nor substantially affects the development of the macrophage lineage both in vitro and in vivo. In contrast, we show it is an important regulator of the scavenger receptor CD36, which has been genetically linked to lipid accumulation in macrophages. Both 15-deoxy-12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-. We show that PPAR- is required for positive effects of its ligands in modulating macrophage lipid metabolism, but that inhibitory effects on cytokine production and inflammation may be receptor independent.
dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation
(PPAR-
12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-
