Peroxisome Proliferator-Activated Receptors (PPARs) Activation as Therapeutic Targets in Skin Inflammation

Peroxisome proliferator-activated receptors (PPARs) are fatty acid activated transcription factors that belong to the nuclear hormone receptor family. They are initially known as transcriptional regulators of lipid and glucose metabolism, although further evidence has also been accumulated for other functions. Due to the nature of all PPAR isotypes which are expressed and exert effects by regulating the functions of cell types residing and infiltrating in the skin, PPARs represent a major research target for the understanding and treatment of many skin diseases. Atopic dermatitis (AD) is a chronic and relapsing disease characterized by skin barrier dysfunction and immune dysregulation. Skin barrier disturbance is one of the exacerbation factors of AD, due to facile penetration of molecules such as antigens. From the aspect of immune dysregulation, innate and acquired immunity including cell proliferation, cell differentiation, and cytokine network are involved in the pathogenesis. In this review, the role of PPAR in AD and the possibility of its agonist for the treatment of AD are discussed.

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PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming

International Journal of Molecular Sciences ◽

10.3390/ijms22147354 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7354

Author(s):

Stefan Blunder ◽

Petra Pavel ◽

Deborah Minzaghi ◽

Sandrine Dubrac

Keyword(s):

Atopic Dermatitis ◽

Hormone Receptors ◽

Target Genes ◽

Skin Diseases ◽

Retinoic Acid Receptor ◽

Skin Inflammation ◽

Nuclear Hormone Receptor ◽

Peroxisome Proliferator ◽

Keratinocyte Proliferation ◽

Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), β or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARβ/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARβ/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARβ/δ to alleviate skin inflammation is discussed.

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The Efficacy and Safety of Dual-Frequency Ultrasound for Improving Skin Hydration and Erythema in Patients with Rosacea and Acne

Journal of Clinical Medicine ◽

10.3390/jcm10040834 ◽

2021 ◽

Vol 10 (4) ◽

pp. 834

Author(s):

Young Jae Kim ◽

Ik Jun Moon ◽

Hae Woong Lee ◽

Chong Hyun Won ◽

Sung Eun Chang ◽

...

Keyword(s):

Skin Diseases ◽

Skin Barrier ◽

Skin Hydration ◽

Efficacy And Safety ◽

Dual Frequency ◽

Barrier Dysfunction ◽

Inflammatory Skin Diseases ◽

Facial Erythema ◽

Frequency Ultrasound

Inflammatory skin diseases, such as rosacea and acne, are major causes of facial erythema and accompanying skin barrier dysfunction. Several methods to restore the impaired skin barrier and improve facial erythema, such as medication, radiofrequency, laser, and ultrasound therapy were attempted. This study evaluated the efficacy and safety of dual-frequency ultrasound with impulse mode, for improving skin hydration and erythema in Asian subjects with rosacea and acne. Twenty-six subjects with facial erythema received an ultrasound treatment once per week, for 4 weeks, over both cheeks. The erythema index and transepidermal water loss (TEWL) were measured at each visit. Clinicians assessed the erythema improvement and patients evaluated their satisfaction level. The average decrease in TEWL and erythema index at 6 weeks was 5.37 ± 13.22 g·h−1·m−2 (p = 0.020) and 39.73 ± 44.21 (p = 0.010), respectively. The clinician’s erythema assessment and the subject satisfaction questionnaire score significantly improved at final follow-up (p < 0.001; p = 0.003, respectively). No serious adverse effects were observed during the treatment and follow-up periods. The dual-frequency ultrasound with impulse mode appears to be effective and safe for improving skin hydration and erythema in patients with rosacea and acne.

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Eucalyptus citriodora extract regulates cutaneous homeostasis including immune dysregulation and skin barrier dysfunction via the modulation of peroxisome proliferator-activated receptor-delta (PPAR-delata) pathway

Trends in Immunotherapy ◽

10.24294/ti.v3.i1.1130 ◽

2019 ◽

Vol 3 (1) ◽

Author(s):

Akihiro Aioi ◽

Takuhiro Yamada

Keyword(s):

Mrna Expression ◽

Skin Barrier ◽

Immune Dysregulation ◽

Keratinocyte Differentiation ◽

Hacat Cells ◽

Skin Disorders ◽

Eucalyptus Citriodora ◽

Barrier Dysfunction ◽

Differentiation Markers ◽

Transfected Cells

Perturbation of cutaneous homeostasis including immune dysregulation and skin barrier dysfunction evokes skin disorders. In this study, we examined the effect of Eucalyptus citriodora (Euc-c) extract on cytokine production, cell proliferation and cell differentiation in HaCaT cells to elucidate its influence on cutaneous homeostasis. Euc-c suppressed significantly LPS-induced IL-6 and TNF-a-induced IL-8 production from HaCaT cells. Conversely IL-1ra production was significantly enhanced by Euc-c. The expressions of IVL, CERS3 and CERS4, keratinocyte differentiation markers, were upregulated to 3.1, 2.8 and 2.7-fold respectively by Euc-c treatment, compared to the control, while the proliferation was downregulated. The lipid contents in Euc-c-treated cells tended to increase, compared with non-treated cells. To explore the underlying mechanism of these effect, we next performed siRNA experiments against PPAR-b/d. Euc-c enhanced PPAR-b/d mRNA expression to 3.25-fold, while PPAR-b/d mRNA expression in transfected cells was suppressed. The expressions of IVL, CERS3 and CERS4 in transfected cells were suppressed to 1.48, 0.82 and 0.72-fold respectively, concomitant with suppression of PPAR-b/d mRNA expression. These results indicated that Euc-c exerts anti-inflammatory effects and regulates keratinocyte differentiation via the modulation of PPAR-b/d pathway. Therefore, the application of Euc-c is expected to exert beneficial effect on skin disorders evoked by perturbation of skin homeostasis.Key words: Eucalyptus citriodora, PPAR-b/d, inflammation, barrier function, cutaneous homeostasis

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Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk

International Journal of Molecular Sciences ◽

10.3390/ijms21072391 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2391 ◽

Cited By ~ 4

Author(s):

Rohit A. Sinha ◽

Sangam Rajak ◽

Brijesh K. Singh ◽

Paul M. Yen

Keyword(s):

Energy Metabolism ◽

Nuclear Hormone Receptor ◽

Peroxisome Proliferator ◽

Reciprocal Regulation ◽

Alcoholic Fatty Liver ◽

Lysosomal Activity ◽

Hepatic Lipid ◽

Peroxisome Proliferator Activated Receptors ◽

Key Aspects ◽

Alcoholic Fatty Liver Disease

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPARα has been implicated in the regulation of autophagy-lysosomal function, which plays a key role in cellular energy metabolism. PPARα transcriptionally upregulates several genes involved in the autophagy-lysosomal degradative pathway that participates in lipolysis of triglycerides within the hepatocytes. Interestingly, a reciprocal regulation of PPARα nuclear action by autophagy-lysosomal activity also exists with implications in lipid metabolism. This review succinctly discusses the unique relationship between PPARα nuclear action and lysosomal activity and explores its impact on hepatic lipid homeostasis under pathological conditions such as non-alcoholic fatty liver disease (NAFLD).

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Skin Barrier Abnormalities and Immune Dysfunction in Atopic Dermatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21082867 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2867 ◽

Cited By ~ 6

Author(s):

Gabsik Yang ◽

Jin Kyung Seok ◽

Han Chang Kang ◽

Yong-Yeon Cho ◽

Hye Suk Lee ◽

...

Keyword(s):

Atopic Dermatitis ◽

Systemic Disease ◽

Skin Barrier ◽

Immune Dysregulation ◽

Food Allergies ◽

Atopic Diseases ◽

Barrier Dysfunction ◽

Underlying Mechanisms ◽

Chronic Pruritus ◽

And Function

Atopic dermatitis (AD) is a common and relapsing skin disease that is characterized by skin barrier dysfunction, inflammation, and chronic pruritus. While AD was previously thought to occur primarily in children, increasing evidence suggests that AD is more common in adults than previously assumed. Accumulating evidence from experimental, genetic, and clinical studies indicates that AD expression is a precondition for the later development of other atopic diseases, such as asthma, food allergies, and allergic rhinitis. Although the exact mechanisms of the disease pathogenesis remain unclear, it is evident that both cutaneous barrier dysfunction and immune dysregulation are critical etiologies of AD pathology. This review explores recent findings on AD and the possible underlying mechanisms involved in its pathogenesis, which is characterized by dysregulation of immunological and skin barrier integrity and function, supporting the idea that AD is a systemic disease. These findings provide further insights for therapeutic developments aiming to repair the skin barrier and decrease inflammation.

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The Role of Peroxisome Proliferator-Activated Receptors in Pulmonary Vascular Disease

PPAR Research ◽

10.1155/2007/18797 ◽

2007 ◽

Vol 2007 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Rachel E. Nisbet ◽

Roy L. Sutliff ◽

C. Michael Hart

Keyword(s):

Pulmonary Hypertension ◽

Vascular Disease ◽

Vascular Dysfunction ◽

Treatment Strategies ◽

Underlying Disease ◽

Nuclear Hormone Receptor ◽

Pulmonary Vascular Disease ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptors ◽

And Function

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated in pulmonary vascular dysfunction and evidence that PPARs, in particular PPARγ, participate in their regulation and may provide a potential novel therapeutic target for the treatment of pulmonary hypertension.

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Peroxisome Proliferator-Activated Receptors and Shock State

The Scientific World JOURNAL ◽

10.1100/tsw.2006.298 ◽

2006 ◽

Vol 6 ◽

pp. 1770-1782 ◽

Cited By ~ 7

Author(s):

Emanuela Esposito ◽

Salvatore Cuzzocrea ◽

Rosaria Meli

Keyword(s):

Transcription Factors ◽

Energy Homeostasis ◽

Hormone Receptors ◽

Inflammatory Responses ◽

Nuclear Hormone Receptor ◽

Peroxisome Proliferator ◽

Shock State ◽

Anti Inflammatory ◽

Peroxisome Proliferator Activated Receptors ◽

Inflammatory Molecules

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. Three isotypes of PPARs have been identified: alpha, beta/delta, and gamma, encoded by different genes and distributed in various tissues. PPARs are implicated in the control of inflammatory responses and in energy homeostasis and, thus, can be defined as metabolic and anti-inflammatory transcription factors. They exert anti-inflammatory effects by inhibiting the induction of proinflammatory cytokines, adhesion molecules, and extracellular matrix proteins, or by stimulating the production of anti-inflammatory molecules. Moreover, PPARs modulate the proliferation, differentiation, and survival of immune cells. This review presents the current state of knowledge regarding the involvement of PPARs in the control of inflammatory response, and their potential therapeutic applications in several types of shock, as well as hemorrhagic, septic, and nonseptic shock.

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Differential Expression of Peroxisome Proliferator-activated Receptors (PPARs) in the Developing Human Fetal Digestive Tract

Journal of Histochemistry & Cytochemistry ◽

10.1177/002215540004800504 ◽

2000 ◽

Vol 48 (5) ◽

pp. 603-611 ◽

Cited By ~ 61

Author(s):

Cécile Huin ◽

Lina Corriveau ◽

Arnaud Bianchi ◽

Jean Marie Keller ◽

Philippe Collet ◽

...

Keyword(s):

Digestive Tract ◽

Polyclonal Antibodies ◽

Cell Types ◽

Peroxisome Proliferator ◽

Protection Assay ◽

Peroxisome Proliferator Activated Receptor ◽

Mesodermal Origin ◽

Peroxisome Proliferator Activated Receptors ◽

Human Digestive Tract ◽

High Level

SUMMARY We investigated the spatiotemporal distributions of the different peroxisome proliferator-activated receptor (PPAR) isotypes (α, β, and α) during development (Week 7 to Week 22 of gestation) of the human fetal digestive tract by immunohistochemistry using specific polyclonal antibodies. The PPAR subtypes, including PPARα, are expressed as early as 7 weeks of development in cell types of endodermal and mesodermal origin. The presence of PPARα was also found by Western blotting and nuclease-S1 protection assay, confirming that this subtype is not adipocyte-specific. PPARα, PPARβ, and PPARα exhibit different patterns of expression during morphogenesis of the digestive tract. Whatever the stage and the gut region (except the stomach) examined, PPARα is expressed at a high level, suggesting some fundamental role for this receptor in development and/or physiology of the human digestive tract.

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Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis

Journal of Clinical Medicine ◽

10.3390/jcm9113741 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3741

Author(s):

Masutaka Furue

Keyword(s):

Atopic Dermatitis ◽

Barrier Function ◽

Coal Tar ◽

Calcineurin Inhibitors ◽

Skin Barrier ◽

Skin Inflammation ◽

Interleukin 4 ◽

Skin Barrier Function ◽

Barrier Dysfunction ◽

Therapeutic Implications

Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction, and chronic pruritus. As the anti-interleukin-4 (IL-4) receptor α antibody dupilumab improves all three cardinal features of AD, the type 2 cytokines IL-4 and especially IL-13 have been indicated to have pathogenic significance in AD. Accumulating evidence has shown that the skin barrier function is regulated via competition between the aryl hydrocarbon receptor (AHR) axis (up-regulation of barrier) and the IL-13/IL-4‒JAK‒STAT6/STAT3 axis (down-regulation of barrier). This latter axis also induces oxidative stress, which exacerbates inflammation. Conventional and recently developed agents for treating AD such as steroid, calcineurin inhibitors, cyclosporine, dupilumab, and JAK inhibitors inhibit the IL-13/IL-4‒JAK‒STAT6/STAT3 axis, while older remedies such as coal tar and glyteer are antioxidative AHR agonists. In this article, I summarize the pathogenic and therapeutic implications of the IL-13/IL-4‒JAK‒STAT6/STAT3 axis and the AHR axis in AD.

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