PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation

Ajay Chawla; Yaacov Barak; Laszlo Nagy; Debbie Liao; Peter Tontonoz; Ronald M. Evans

doi:10.1038/83336

PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation

Ajay Chawla, Yaacov Barak, Laszlo Nagy, Debbie Liao, Peter Tontonoz, Ronald M. Evans

Research output: Contribution to journal › Article › peer-review

936 Scopus citations

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ) 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-γ in macrophage function and disease progression. To define the role of PPAR-γ in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-γ gene. We demonstrate here that PPAR-γ 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-δ¹²,¹⁴prostaglandin J₂ and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-γ. We show that PPAR-γ 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.

Original language	English (US)
Pages (from-to)	48-52
Number of pages	5
Journal	Nature medicine
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/83336
State	Published - 2001
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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title = "PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation",

abstract = "Peroxisome proliferator-activated receptor-γ (PPAR-γ) 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-γ in macrophage function and disease progression. To define the role of PPAR-γ in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-γ gene. We demonstrate here that PPAR-γ 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-δ12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-γ. We show that PPAR-γ 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.",

author = "Ajay Chawla and Yaacov Barak and Laszlo Nagy and Debbie Liao and Peter Tontonoz and Evans, {Ronald M.}",

note = "Funding Information: Acknowledgments We thank G. Keller for assistance with ES-cell differentiation and S. Gordon for assistance with macrophage analysis. This work was supported by NIH Grant #2 T32 HL07770 (to A.C.), the Boehringer Ingelheim Research Award (to L.N.), and a grant from the UCLA Jonsson Comprehensive Cancer Center (to P.T.).",

year = "2001",

doi = "10.1038/83336",

language = "English (US)",

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pages = "48--52",

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T1 - PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation

AU - Chawla, Ajay

AU - Barak, Yaacov

AU - Nagy, Laszlo

AU - Liao, Debbie

AU - Tontonoz, Peter

AU - Evans, Ronald M.

N1 - Funding Information: Acknowledgments We thank G. Keller for assistance with ES-cell differentiation and S. Gordon for assistance with macrophage analysis. This work was supported by NIH Grant #2 T32 HL07770 (to A.C.), the Boehringer Ingelheim Research Award (to L.N.), and a grant from the UCLA Jonsson Comprehensive Cancer Center (to P.T.).

PY - 2001

Y1 - 2001

N2 - Peroxisome proliferator-activated receptor-γ (PPAR-γ) 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-γ in macrophage function and disease progression. To define the role of PPAR-γ in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-γ gene. We demonstrate here that PPAR-γ 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-δ12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-γ. We show that PPAR-γ 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.

AB - Peroxisome proliferator-activated receptor-γ (PPAR-γ) 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-γ in macrophage function and disease progression. To define the role of PPAR-γ in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-γ gene. We demonstrate here that PPAR-γ 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-δ12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-γ. We show that PPAR-γ 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.

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PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation

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