Peroxisome Proliferator-Activated Receptors and Skin Development

Abstract

PPARs are nuclear hormone receptors. PPAR subtypes (α, γ, δ, the latter a xPPARβ homologue) were initially investigated in skin because of their known role in regulating lipid metabolism. Studies adding specific PPAR ligand activators to cultured skin or skin cells are compatible with the concepts that PPARα activation mediates early lipogenic steps common to the function of both skin epidermal cells (keratinocytes) and sebaceous cells (sebocytes), PPARγ activation plays a unique role in stimulating sebocyte lipogenesis, and PPARδ activation may contribute to lipid biosynthesis in both sebocytes and keratinocytes under certain circumstances. Epidermal keratinocytes appear to express small amounts of PPARα and PPARδ mRNA and a trace of PPARγ mRNA which is up-regulated with differentiation. Sebocytes express all subtypes; PPARγ gene expression excedes that in epidermis. The emerging data on PPAR protein expression suggests that epidermis normally expresses predominantly PPARα, while sebocytes express more PPARγ than PPARα. These expression patterns may change during hyperplasia, differentiation and inflammation. Gene disruption studies in mice are compatible with a contribution of PPARα to skin barrier function, suggest that PPARγ is necessary for sebocyte differentiation, and indicate that PPARδ can ameliorate inflammatory responses in skin. PPARs appear to play a role in keratinocyte synthesis of the lipids that they export to the intercellular space to form the skin permeability barrier. They also appear to be important for sebocyte formation of the intracellular fused lipid droplets that constitute the holocrine secretion of the sebaceous gland. In addition, they may play roles in keratinocyte growth and differentiation and the inhibition of skin inflammation by diverse mechanisms not necessarily related to fat metabolism.

Hedgehog Signaling Regulates Sebaceous Gland Development

“…The potential influence of cross-talk involving Hedgehog and Wnt 49 or BMP 50 pathways will also need to be examined. In addition, it will be important to explore the relationship between the Hedgehog pathway and other molecules implicated in sebocyte development, including c-Myc, 36,37 PPAR␥, 51,52 and COX-2. 53 Hair follicles and sebaceous glands both undergo cyclic changes after birth, 54 and Shh plays a major role in regulating proliferation of follicle epithelium during times of active growth.…”

Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents

“…A possible mechanism of these effects was described : soluble Jagged-1 peptides induce rapid and transient activation of NF-kB, followed by induction of PPARg, which in turn neutralizes NF-kB. Both NF-kB and PPAR transcription factors are thought to be necessary for keratinocyte differentiation Rosenfield et al, 2000). Which of the Notch isoforms is responsible for these effects is still unclear, as is the mechanism of direct activation of NF-kB by Jagged ligands.…”

Human Skin: An Independent Peripheral Endocrine Organ

“…The second group, the thyroid receptor family, includes the thyroid hormone receptors (isotypes α1 and β1), whereas the isotype β1 is present in epidermal keratinocytes, outer root sheat cells, cebocytes, dermal papilla cells, and dermal fibroblasts [6, 52, 53], the estrogen receptor-β (but not the estrogen receptor-α) which is expressed in dermal papilla cells and dermal fibroblasts, sebocytes, adipocytes, melanocytes, and keratinocytes of the outer root sheath [48, 54, 55, 56], the retinoic acid receptors (RAR; isotypes α and γ) and retinoid X receptors (RXR; isotypes α, β, γ) which are expressed in epidermal keratinocytes of the stratum granulosum, follicular keratinocytes, sebocytes, and endothelial cells, while only the RXRα isotype is present in melanocytes, fibroblasts, and inflammatory cells [57, 58, 59, 60, 61], the vitamin D receptor which is present in keratinocytes of all epidermal layers except those of the stratum corneum, epithelial cells of the epidermal appendages, melanocytes, Langerhans cells, CD11b+ macrophages and CD3+ T-lymphocytes [62, 63], and the peroxisome proliferator-related receptors (PPAR) which are expressed in epidermal and follicular keratinocytes, sebocytes, sweat gland cells, endothelial cells, and adipocytes (isotype γ), whereas isotypes α and δ are also expressed in keratinocytes and sebocytes [64]. The members of the thyroid receptor family share a high degree of homology to the proto-oncogene c-erb A and high affinity for a common DNA recognition site.…”