The role of peroxisome proliferator-activated receptors (PPAR) in immune responses

doi:10.1016/j.metabol.2020.154338

Metabolism

Volume 114, January 2021, 154338

https://doi.org/10.1016/j.metabol.2020.154338 Get rights and content

Highlights

•
PPAR in the function on innate immune cells
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PPAR function on adaptive immune cells
•
PPAR role in immune-mediated inflammatory conditions
•
PPAR therapeutic options in immunology

Abstract

Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors of nuclear hormone receptor superfamily that regulate energy metabolism. Currently, three PPAR subtypes have been identified: PPARα, PPARγ, and PPARβ/δ. PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery and oxidative phosphorylation (OXPHOS) and regulation of energy homeostasis. In contrast, PPARγ is more important in lipogenesis and lipid synthesis, with highest expression levels in white adipose tissue (WAT). In addition to tissues regulating whole body energy homeostasis, PPARs are expressed in immune cells and have an emerging critical role in immune cell differentiation and fate commitment. In this review, we discuss the actions of PPARs in the function of the innate and the adaptive immune system and their implications in immune-mediated inflammatory conditions.

Section snippets

Introduction: structure and classification of PPARs

The transcription factors Peroxisome proliferator activated receptors (PPARs) were discovered 30 years ago in rodents [1] and belong to the subfamily 1 of the nuclear hormone receptor superfamily of transcription factors [2]. PPARs are the best-studied fatty acid-activated nuclear receptors comprising of the following three subtypes: PPARα, PPARγ, and PPARδ (also designated as PPARβ) [[3], [4], [5], [6], [7], [8]]. Although all PPARs play a major regulatory role in energy homeostasis each of

Function of PPARs on lipid metabolism

PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery, substrate oxidation, and oxidative phosphorylation (OXPHOS) [3,9]. PPARα is expressed mainly in the liver, heart, skeletal muscles, brown adipose tissue (BAT), intestine and kidney and activates energy dissipation. PPARα mediates its functions by influencing fatty acid transport, esterification and oxidation. PPARβ/δ is expressed ubiquitously and participates in fatty acid oxidation, but

Function of PPARs on innate and adaptive immune cells

In the past few years, the role of PPARs in immune cells has been extensively studied. As key regulators of metabolism, PPARs guide the differentiation, expansion and fate commitment of various immune cell types. These effects have significant implications in organs that become targets of immunometabolic aberrations induced upon dysfunction of PPAR members.

PPARγ

The function of PPARγ has been associated with several inflammatory and autoimmune conditions. PPARγ null mice develop anti-phospholipid syndrome, an autoimmune disorder associated with glomerular injury and microthrombi [95]. The relationship between PPARγ and anti-phospholipid syndrome is not surprising since hemizygote T cell-specific [96] or myeloid cell-specific deletion [97] of PPARγ is associated with lupus-like glomerular damage. Mice with PPARγ deletion in the T cell compartment

Therapeutic exploitation of PPARs

As multifunctional molecules, PPARs are implicated in a variety of a human diseases such as cancer [[138], [139], [140]], metabolic [141] and autoimmune conditions [142]. Therapeutic targeting of PPARs has been attempted in several of these conditions. Several synthetic exogenous ligands of PPAR receptors have been developed and therapeutically exploited (Table 2). Fibrates consist of a large group of synthetic PPARα agonists used for the treatment of hypertriglyceridemia, while TZD is a group

Concluding remarks

Members of the PPAR family of nuclear hormone receptors are well-established regulators of lipid metabolism, mitochondrial biogenesis and energy homeostasis. Their activation has central implications in the function of oxidative tissues and organs such as cardiomyocytes, liver and muscle. For many years, PPARs have been attractive therapeutic targets for the treatment of metabolic disorders. The role of various members of this nuclear receptor family is currently emerging in the differentiation

Author contribution

AC, performed literature review and generated the main draft of the manuscript; EK, CJ performed literature review and generated sections of the manuscript. VB provided guidance, performed literature review and prepared the final manuscript and figures.

Declaration of competing interest

The authors do not have relevant conflicts of interest to disclose.

Acknowledgments

This work was supported by the National Institutes of Health awards: RO1CA212605, RO1CA238263 and RO1CA229784 (VAB).

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ReviewThe role of peroxisome proliferator-activated receptors (PPAR) in immune responses

Highlights

Abstract

Section snippets

Introduction: structure and classification of PPARs

Function of PPARs on lipid metabolism

Function of PPARs on innate and adaptive immune cells

PPARγ

Therapeutic exploitation of PPARs

Concluding remarks

Author contribution

Declaration of competing interest

Acknowledgments

Cell

Pharmacol Res

J Biol Chem

Trends Biochem Sci

J Biol Chem

FEBS Lett

J Biol Chem

Cell Metab

Mol Cell

Cell

Mol Cell

Cell

Dev Cell

Exp Cell Res

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Immunity

Immunity

J Biol Chem

Redox Biol

Cell Metab

Mol Cell

J Mol Cell Cardiol

Blood

Biochim Biophys Acta

Cell Metab

Biochem Biophys Res Commun

Brain Res

Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators

Nature

A unified nomenclature system for the nuclear receptor superfamily

Cell

Nuclear receptors and lipid physiology: opening the X-files

Science

The PPARs: from orphan receptors to drug discovery

J Med Chem

Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review

Nutr J

Transcriptional regulation of metabolism

Physiol Rev

International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors

Pharmacol Rev

The mechanisms of action of PPARs

Annu Rev Med

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

Mol Cell Biol

Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARgamma

Nat Commun

Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping

Gene Expr

PPARs: nuclear receptors controlled by, and controlling, nutrient handling through nuclear and cytosolic signaling

PPAR Res

Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression

Endocrinology

Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle

Proc Natl Acad Sci U S A

ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1

Nat Med

Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning

Hepatology

PPARgamma agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

Diabetologia

C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway

Genes Dev

Transcriptional regulatory circuits controlling brown fat development and activation

Diabetes

A truncated PPAR gamma 2 localizes to mitochondria and regulates mitochondrial respiration in brown adipocytes

Review
The role of peroxisome proliferator-activated receptors (PPAR) in immune responses