Search

Summary Peroxisome proliferator-activated receptors are involved in certain cell types such as adipocytes and hepatocytes, in the control of several pathways of lipid synthesis or catabolism by regulating the gene expression level of key lipid metabolizing enzymes. As the epidermis exhibits an extensive lipid metabolism necessary for the establishment of the barrier function, we have examined the role of peroxisome proliferator-activated receptor-α activation in this process. Living skin equivalents were treated with Wy 14,643, a selective peroxisome proliferator- activated receptor-α ligand, which enhanced greatly the synthesis of membrane coating granules, the organelles specialized in the processing of stratum corneum lipids. Also, the overall stratum corneum neutral lipid content assessed by Oil red O staining was increased. A detailed analysis of the lipid species present in the reconstructed epidermis showed that peroxisome proliferator-activated receptor-α activation increased the synthesis of ceramides and cholesterol derivatives, thought to be essential structural components of the permeability barrier. A synergistic effect was observed on lipid synthesis when peroxisome proliferator-activated receptor-α and retinoid X receptor were simultaneously activated by selective ligands. Furthermore, activation of peroxisome proliferator-activated receptor-α led to increased mRNA expression of several key enzymes of ceramide and cholesterol metabolism. An increase of serine-palmitoyl transferase and of β-glucocerebrosidase enzymatic activity was also demonstrated. Altogether, these results show that peroxisome proliferator-activated receptor-α is a key transcription factor involved in the control of the epidermal lipid barrier. [ABSTRACT FROM AUTHOR]

The expression of mRNA encoding peroxisome proliferator-activated receptor (PPAR) subtypes in human keratinocytes was determined by semiquantitative reverse transcriptase-polymerase chain reaction. When normal human keratinocytes were induced to differentiate by shifting the culture medium to high Ca2+ concentration, the expression of PPAR-α and -γ mRNA was increased, whereas that of PPAR-δ remained unchanged. At the protein level, the expression of PPAR in cultured human keratinocytes was demonstrated by a DNA mobility shift assay and the functionality of the receptor subtypes was assessed by transactivation experiments. In epidermis reconstructed in vitro, the level of PPAR-α and -γ mRNA was also associated with keratinocyte differentiation. In lesional compared with nonlesional psoriatic epidermis, the expression of PPAR-α and -γ mRNA was reduced, indicating that these two subtypes are tightly linked to the epidermal differentiation process. [ABSTRACT FROM AUTHOR]

Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions. [ABSTRACT FROM AUTHOR]