The Immune Responses of Peroxisome Proliferator-Activated Receptors (Ppar) And Their Therapeutic Ligand-Activated Transcription Factors

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention.

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).

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). 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.

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.

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. 

Therapeutic exploitation of PPARs

As multifunctional molecules, PPARs are implicated in a variety of a human diseases such as cancer, metabolic and autoimmune conditions. 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.

Transcriptional PPAR responses also depend heavily on ligand-induced recruitment or release of small accessory molecules known as coactivators and corepressors, respectively. These cofactors, a large, diverse family involving multiple members such as nuclear corepressor, PPAR-binding protein, PPARγ coactivator, and cAMP response element-binding protein are critical determinants of the cellular PPAR response. This multiprotein complex induces transcription by chromatin remodeling and interaction with the basal transcriptional machinery.

PPARα: A Central Regulator of Fatty Acid Metabolism

PPARα, the first PPAR cloned, plays an important role in regulating the β-oxidation of fatty acids, a major source of cellular energy. Consistent with this, PPARα is expressed primarily in metabolically active, energy-requiring tissues, including liver, heart, skeletal muscle, and kidney. PPARα target genes include multiple proteins essential for fatty acid uptake, intracellular transport, and β-oxidation, including fatty acid transport protein, fatty acid translocase, long-chain fatty acid acetyl-coenzyme A synthase, and carnitine palmitoyl transferase I. PPARα activation induces expression of LPL, which hydrolyzes triglyceride rich lipoproteins, the major source of circulating fatty acids. PPARα also represses apolipoprotein (Apo) CIII expression, which is an endogenous inhibitor of LPL activity.

Vascular Smooth Muscle

PPARα expression in vascular smooth muscle cells (VSMCs) raises similar issues regarding direct PPAR activation, in this case, in a cellular setting relevant to hypertension, atherosclerosis, and restenosis after coronary intervention. PPARα activation reportedly inhibits interleukin-1–stimulated secretion of interleukin-6 by human aortic smooth muscle cells. Consistent with this, synthetic PPARα agonists decrease circulating levels of inflammatory markers and mediators, including interleukin-6, and C-reactive protein.

Monocytes/Macrophages/Lymphocytes

PPARα is expressed in inflammatory cells integral to atherosclerosis like monocytes, macrophages, and lymphocytes. Of note, unlike human macrophages, mice macrophages lack PPARα expression, highlighting the potential complexities in preclinical PPAR studies. Presumably, results from experiments testing PPARα activation in murine macrophages, including responses to PPARα agonists, reflect PPARα-independent effects.

PPAR are involved in various independent and DNA-dependent molecular and enzymatic pathways in adipose tissue, liver, and skeletal muscles. These pathways are affected in disease condition and cause the metabolic energy imbalance. Thus, intervention of PPAR can provide therapeutic targets for plethora of diseases such as dyslipidemia, diabetes, obesity, inflammation, neurodegenerative disorder, and cancer.