PPARs: Fatty acid sensors controlling metabolism

doi:10.1016/j.semcdb.2012.01.003

Seminars in Cell & Developmental Biology

Volume 23, Issue 6, August 2012, Pages 631-639

https://doi.org/10.1016/j.semcdb.2012.01.003 Get rights and content

Abstract

The peroxisome proliferator activated receptors (PPARs) are nuclear receptors that play key roles in the regulation of lipid metabolism, inflammation, cellular growth, and differentiation. The receptors bind and are activated by a broad range of fatty acids and fatty acid derivatives and they thereby serve as major transcriptional sensors of fatty acids. Here we review the function, regulation, and mechanism of the different PPAR subtypes with special emphasis on their role in the regulation of lipid metabolism.

Highlights

► PPARs are molecular sensors of FAs and FA derivatives and control metabolism. ► The three subtypes display distinct but overlapping expression and functions. ► PPARα is a major activator of FAO, e.g. in liver and BAT. ► PPARδ is a major activator of oxidative metabolism and is ubiquitously expressed. ► PPARγ is a major activator of adipogenesis and FA storage.

Section snippets

Structure and basic mechanism of the PPARs

The PPARs are members of the nuclear receptor (NR) superfamily of ligand activated transcription factors [1]. This superfamily is one of the largest groups of metazoan transcription factors and NRs have been found to be involved in a broad range of biological processes including development, reproduction, inflammation, immune function, metabolism, apoptosis, growth, and cancer [1], [2], [3]. The PPARs are found within the vertebrate subphylum in which the ancestral PPAR prototype appears to

Tissue distribution and primary metabolic function of the PPARs

Consistent with the PPARs being major regulators of FA metabolism, they are expressed at high levels in tissues that are most active in lipid metabolism. However, the three PPAR subtypes display highly distinct expression profiles and biochemical properties resulting in subtype selective activation of target genes. The primary metabolic functions and tissue distributions of the three PPAR subtypes are shown in Fig. 3. PPARα is a major inducer of FA oxidation (FAO) and highly expressed in

Conclusion

The three PPAR subtypes share basic mechanisms of action, are activated by overlapping groups of FA derivatives, and share many target genes. However, the different PPAR subtypes also display highly distinct functions in vivo. The functional differences are due in part to the differential expression profiles of the subtypes, in part to the different biochemical properties responsible for the differential integration of the PPAR subtypes into transcriptional complexes and signaling networks.

Acknowledgments

The authors thank members of the Mandrup group for valuable input to this manuscript. This work was supported by the EC through grants to the FP7 project AtheroRemo, by grants from NordForsk to the Nordic Centre of Excellence MitoHealth, and by grants from the Novo Nordisk Foundation. We apologize to the authors of the papers that we could not cite due to space limitations.

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ReviewPPARs: Fatty acid sensors controlling metabolism

Abstract

Highlights

Section snippets

Structure and basic mechanism of the PPARs

Tissue distribution and primary metabolic function of the PPARs

Conclusion

Acknowledgments

Biochim Biophys Acta

Prog Lipid Res

Nat Med

Biochim Biophys Acta

Curr Opin Struct Biol

J Biol Chem

J Biol Chem

J Biol Chem

Mol Cell

J Biol Chem

J Biol Chem

Cell

J Biol Chem

FEBS Lett

J Biol Chem

J Biol Chem

Biochim Biophys Acta

Structure

Biochimie

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cell

Cell Metab

J Biol Chem

Cell

J Urol

Semin Cell Dev Biol

Cell

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cell

J Biol Chem

J Biol Chem

J Lipid Res

Cell Metab

Ligand binding and nuclear receptor evolution

Bioessays

Structure of the intact PPAR-gamma-RXR-alpha nuclear receptor complex on DNA

Nature

Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings

Nat Struct Mol Biol

Molecular mechanisms and genome-wide aspects of PPAR subtype specific transactivation

PPAR Res

Flexible nets. The roles of intrinsic disorder in protein interaction networks

FEBS J

The PPARgamma2 A/B-domain plays a gene-specific role in transactivation and cofactor recruitment

Mol Endocrinol

MED14 tethers mediator to the N-terminal domain of peroxisome proliferator-activated receptor gamma and is required for full transcriptional activity and adipogenesis

Mol Cell Biol

Peroxisome proliferator-activated receptor subtype- and cell-type-specific activation of genomic target genes upon adenoviral transgene delivery

Mol Cell Biol

Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes

Proc Natl Acad Sci USA

Review
PPARs: Fatty acid sensors controlling metabolism