Biomedical subjects

D Deplewski

Publications and source records attributed to D Deplewski.

8 recordsLinked to original sources

PubMed2001

Limited cooperation between peroxisome proliferator-activated receptors and retinoid X receptor agonists in sebocyte growth and development.

We have found that sebaceous epithelial cell (sebocyte) differentiation is induced by cognate ligand-agonists of either peroxisome proliferator-activated receptors (PPARs) or retinoid X receptors (RXRs). In this study, we tested the hypothesis that PPAR-RXR cooperation is used in sebocytes as was reported to occur in gene transfection systems and liposarcoma cells through PPAR-RXR heterodimerization. PPAR agonists at maximally effective concentrations were tested in combination with a specific RXR agonist (the rexinoid CD2809) at doses ranging from submaximal to maximal in a primary rat preputial cell monolayer culture system. We evaluated ligand-agonists of PPARalpha (WY-14643 = WY), PPARgamma (troglitazone = TRO), and PPARdelta,alpha (carbaprostacyclin = cPGI2). Cell differentiation was determined by analysis of lipid staining and proliferation by cell counting. The RXR agonist induced a more diffuse and granular pattern of lipid staining throughout colonies than did PPAR agonists. The PPAR ligands WY, TRO, and cPGI2 induced 37, 35, and 59% lipid-forming colonies (LFCs), respectively (P < 0.05 vs controls, which averaged 19%). Low-dose rexinoid (10(-8) M) alone exerted no significant effect but amplified the effect of cPGI2 (P < 0.05). Middose rexinoid (10(-7) M), which alone induced about 40% LFCs, had an additive effect on differentiation with WY, TRO, and cPGI2 (71, 48, and 83% LFCs respectively, P < 0.05 vs each agonist alone). Proliferation was enhanced significantly by either rexinoid or cPGI2, but there was no change in growth when the two were added together. The greater effectiveness of cPGI2 than the other PPAR agonists may be explained by the predominance of PPARdelta gene expression in cultured sebocytes, as demonstrated by RNase protection assay. These studies demonstrate that a submaximal dose of RXR agonist augmented the stimulation of sebocyte differentiation by PPAR agonists, as expected from PPAR-RXR heterodimerization. However, the evidence for PPAR-RXR cooperativity is limited. The pattern of lipid staining is compatible with an independent effect of rexinoid on sebocyte differentiation. Furthermore, since there is no enhancement of the growth-promoting effects of RXR agonist and cPGI2 when they are combined, this effect also does not appear to be mediated by PPAR-RXR interaction.

Animals↗

PubMed2000

Peroxisome proliferator-activated receptors and skin development.

PPARs are nuclear hormone receptors. PPAR subtypes (alpha, gamma, delta, the latter a xPPARbeta 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 PPARalpha activation mediates early lipogenic steps common to the function of both skin epidermal cells (keratinocytes) and sebaceous cells (sebocytes), PPARgamma activation plays a unique role in stimulating sebocyte lipogenesis, and PPARdelta activation may contribute to lipid biosynthesis in both sebocytes and keratinocytes under certain circumstances. Epidermal keratinocytes appear to express small amounts of PPARalpha and PPARdelta mRNA and a trace of PPARgamma mRNA which is up-regulated with differentiation. Sebocytes express all subtypes; PPARgamma gene expression excedes that in epidermis. The emerging data on PPAR protein expression suggests that epidermis normally expresses predominantly PPARalpha, while sebocytes express more PPARgamma than PPARalpha. These expression patterns may change during hyperplasia, differentiation and inflammation. Gene disruption studies in mice are compatible with a contribution of PPARalpha to skin barrier function, suggest that PPARgamma is necessary for sebocyte differentiation, and indicate that PPARdelta 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.

Animals↗

PubMed2000

Role of hormones in pilosebaceous unit development.

Androgens are required for sexual hair and sebaceous gland development. However, pilosebaceous unit (PSU) growth and differentiation require the interaction of androgen with numerous other biological factors. The pattern of PSU responsiveness to androgen is determined in the embryo. Hair follicle growth involves close reciprocal epithelial-stromal interactions that recapitulate ontogeny; these interactions are necessary for optimal hair growth in culture. Peroxisome proliferator-activated receptors (PPARs) and retinoids have recently been found to specifically affect sebaceous cell growth and differentiation. Many other hormones such as GH, insulin-like growth factors, insulin, glucocorticoids, estrogen, and thyroid hormone play important roles in PSU growth and development. The biological and endocrinological basis of PSU development and the hormonal treatment of the PSU disorders hirsutism, acne vulgaris, and pattern alopecia are reviewed. Improved understanding of the multiplicity of factors involved in normal PSU growth and differentiation will be necessary to provide optimal treatment approaches for these disorders.

Acne Vulgaris↗

PubMed1999

Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors.

The hallmark of sebaceous epithelial cell (sebocyte) differentiation is the accumulation of fused neutral fat droplets. Very little sebocyte differentiation occurs, however, in primary or organ culture, even upon incubating with androgens, which are required for maturation in vivo. We hypothesized that sebocyte cell culture systems lack activators of the peroxisome proliferator-activated receptors that are involved in adipocyte differentiation. We here report that activation of peroxisome proliferator-activated receptor gamma and alpha by their respective specific ligands, a thiazolidinedione and a fibrate, induced lipid droplet formation in sebocytes but not epidermal cells. Linoleic acid and carbaprostacyclin, both peroxisome proliferator-activated receptor delta and alpha ligand-activators, were more effective but less specific, stimulating lipid formation in both types of cells. Either was more effective than the combination of peroxisome proliferator-activated receptor gamma and alpha activation, suggesting that peroxisome proliferator-activated receptor delta is involved in this lipid formation. Linoleic acid 0.1 mM stimulated significantly more advanced sebocyte maturation than any other treatment, including carbaprostacyclin, which suggests a distinct role of long chain fatty acids in sebocyte differentiation. Peroxisome proliferator-activated receptor gammal mRNA was demonstrated in sebocytes, but not in epidermal cells; it was more strongly expressed in freshly dispersed than in cultured sebocytes. In contrast, peroxisome proliferator-activated receptor delta mRNA was expressed to a similarly high extent before and after culture in both sebocytes and epidermal cells. These findings are compatible with the concepts that peroxisome proliferator-activated receptor gamma1 gene expression plays a unique role in the differentiation of sebocytes, while peroxisome proliferator-activated receptor delta activation and long chain fatty acids finalize sebocyte maturation and are capable of stimulating epidermal lipid formation. These findings have implications for the development of new modalities of treatment for acne vulgaris.

Animals↗

PubMed1999

Growth hormone and insulin-like growth factors have different effects on sebaceous cell growth and differentiation.

Several observations suggest that GH stimulates sebaceous gland growth and development. Therefore, we studied the effects of GH and insulin-like growth factors (IGFs), alone and with androgen, on sebaceous epithelial cell (sebocyte) growth and differentiation in vitro. The rat preputial cell culture model system was used to judge differentiation (induction of lipid-forming colonies, LFCs) and DNA synthesis. GH increased sebocyte differentiation. At a dose of 10(-8) M in the presence of micromolar insulin, GH was 3.8 times more potent than IGF-I (38.1+/-4.2%, SEM, vs. 10+/-1.5% LFCs) and 6 times more potent than IGF-II (6+/-0.5% LFCs). IGF-I 10(-8) M alone stimulated a similar amount of differentiation as insulin 10(-6) M, although it was less effective than insulin in augmenting the effect of GH on differentiation. GH had no effect on sebocyte uptake of 3H-thymidine at doses up to 10(-6) M. On the other hand, IGF-I was the most potent stimulus of DNA synthesis (168% of control; P < 0.001 vs. all others). IGF-II 10(-8) M stimulated 3H-thymidine incorporation similarly to insulin 10(-6) M. In the presence of insulin, dihydrotestosterone (DHT) 10(-6) M induced 31.4+/-1.7% LFCs, and there was a tendency of DHT and GH to interact in promoting differentiation. When insulin was omitted from the system, differentiation was decreased overall, but GH +/- DHT slightly improved differentiation. The IGFs had no effect on the response to DHT. DHT decreased DNA synthesis by 40%, an effect unaltered by GH or IGFs. These results suggest that GH and IGFs have different functions in sebaceous cell growth and differentiation: GH stimulated differentiation beyond that found with IGFs or insulin, yet had no effect on DNA synthesis, a parameter stimulated most potently by IGF-I. While GH augmented the effect of DHT on differentiation, the IGFs had no effect on the response of DHT. These data indicate that GH may in part act directly on sebocytes rather than indirectly through IGF production. These data are consistent with the concept that increases in GH and IGF production contribute in complementary ways to the increase in sebum production during puberty and in acromegaly.

Animals↗

PubMed1998

Mechanisms of androgen induction of sebocyte differentiation.

It has been difficult to induce the expected sebocyte differentiation in vitro with dihydrotestosterone (DHT). We reasoned that our culture system lacks differentiating factors, and peroxisome proliferator-activated receptors (PPARs) were the prime candidates. We tested PPAR activators informative about diverse PPAR subtypes, with and without DHT (10(-6) M): BRL-49653 (10(-6) M, PPAR-gamma), WY-14643 (10(-6) M, PPAR-alpha), and linoleic acid (LIN, 10(-4) M, PPAR-delta). Treatments were added in serum-free medium to cultures of rat preputial sebocytes. Control, DHT, BRL and BRL + DHT treatments caused 11, 25, 66 and 80%, respectively, of preputial cell colonies to differentiate into lipid-forming colonies (LFCs) (p < 0.001). WY induced 20% and LIN over 95% LFC formation. PPAR-gamma mRNA was identified in preputial sebocytes by the RNase protection assay. These data suggest that differentiation of sebocytes is transduced by PPARs and have implications for the development of new treatments for acne.

Androgens↗

PubMed1997

Preputial sebocyte 5alpha-reductase isoform specificity.

We determined whether the 5alpha-reductase (5alpha-R) isozyme specificity in rat preputial sebocytes is in accordance with that of sebaceous glands (type 1 isoform) or with that of other genital tract androgen-dependent organs (type 2). Immunostaining indicated expression of type 1 5alpha-R in preputial epithelial cells in the gland as well as in culture. Northern blots and ribonuclease protection assays both showed the presence of the type 1 isozyme in preputial sebocytes, with little if any expression of the type 2 messenger RNA. Ribonuclease protection assay demonstrated that both homogenized preputial gland and freshly dispersed preputial cells express 2-fold more 5alpha-R type 1 messenger RNA than does skin and 7-fold more than cultured preputial cells. Since cultured preputial cells do not fully differentiate in monolayer culture, these findings suggest that 5alpha-R is increasingly expressed as sebaceous cells differentiate. The predominance of the type 1 isoform in preputial sebocytes is important because it indicates programming by a skin- and sebocyte-specific signal in the midst of the genital tract where the type 2 isoform otherwise predominates.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1995

Role of androgens in the developmental biology of the pilosebaceous unit.

The growth and development of pilosebaceous units in their characteristic pattern depends on the interaction of androgens and diverse biologic factors. Stromal-epithelial interactions are essential features. Considerable evidence suggests that androgens stimulate the growth of sensitive pilosebaceous units primarily by acting on specific stromal cells and that androgens and retinoic acid interact to regulate specific stages of sebocyte differentiation.

Androgens↗