The role of PPARγ‐mediated signalling in skin biology and pathology: new targets and opportunities for clinical dermatology

Abstract

Yuval Ramot and Arianna Mastrofrancesco contributed equally to this work.Abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that modulate the expression of multiple different genes involved in the regulation of lipid, glucose and amino acid metabolism. PPARs and cognate ligands also regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. This includes a role in mediating skin and pilosebaceous unit homoeostasis: PPARs appear to be essential for maintaining skin barrier permeability, inhibit keratinocyte cell growth, promote keratinocyte terminal differentiation and regulate skin inflammation. They also may have protective effects on human hair follicle (HFs) epithelial stem cells, while defects in PPARc-mediated signalling may promote the death of these stem cells and thus facilitate the development of cicatricial alopecia (lichen planopilaris). Overall, however, selected PPARc modulators appear to act as hair growth inhibitors that reduce the proliferation and promote apoptosis of hair matrix keratinocytes. The fact that commonly prescribed PPARc-modulatory drugs of the thiazolidine-2,4-dione class can exhibit a battery of adverse cutaneous effects underscores the importance of distinguishing beneficial from clinically undesired cutaneous activities of PPARc ligands and to better understand on the molecular level how PPARc-regulated cutaneous lipid metabolism and PPARcmediated signalling impact on human skin physiology and pathology. Surely, the therapeutic potential that endogenous and exogenous PPARc modulators may possess in selected skin diseases, ranging from chronic inflammatory hyperproliferative dermatoses like psoriasis and atopic dermatitis, via scarring alopecia and acne can only be harnessed if the complexities of PPARc signalling in human skin and its appendages are systematically dissected.

PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

“…Since all PPARs are widely expressed in human skin and its appendages, there is increasing interest in their role in maintaining cutaneous homeostasis and in dermatological disorders . PPAR‐mediated signalling has attracted special interest in psoriasis, atopic dermatitis, acne, skin ageing, scleroderma, melasma, lipodystrophy and skin cancer . In the context of this Focus Theme Issue , this development encourages one to also take a closer look at why and how exactly PPARs are of special interest in a translational hair research context, with a strict focus on their best‐investigated isoform, PPAR‐γ.…”

“…PPARs are nuclear hormone receptors abundantly expressed in tissues that display high fatty acid metabolism, including human skin and its appendages . Three different isoforms of PPARs exist—PPAR‐α, PPAR‐β/δ and PPAR‐γ, which demonstrate diverse functional capabilities, including—to name but a few examples—the control of lipogenesis, cell cycle and inflammatory gene expression (Figure ) …”

Cholesterol homeostasis: Links to hair follicle biology and hair disorders

“…Dysregulation or dysfunction in the PPAR family of ligand‐activated nuclear receptors is also suggested to be a causative factor in PCA . Regulation of cholesterol homeostasis is the domain of numerous nuclear hormone receptors and the PPARs represent one such important pathway . PPAR heterodimerisation with retinoid X receptor (RXR) initiates binding to PPRE (peroxisome proliferator response element), enhancing proliferation of peroxisomes, which act as secondary sites for cholesterol synthesis .…”

“…In the HF, specific PPAR isoforms have roles in HF survival (PPARα), morphogenesis (PPARβ/δ) and keratinocyte differentiation (PPARγ) . PPARγ agonism can reduce IL‐6 and increases keratin 15 levels in the bulge, as well as inducing catagen …”

Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts

“…Several prostaglandins and enzymatic n-3 PUFA metabolites are regulators of the PPAR transcriptional coactivators which regulate skin homeostasis and UV responses [62], and PPARG apparently counteracts UVB induced inflammation [63]. Upon UV exposure, the PPARG agonist 1-alkyl-2-azelaoyl-PC can form non-enzymatically, is active when still esterified to the PL [52] but can also be cleaved by PLA2 to release free azelaic acid [64].…”