Peroxisome proliferator-activated receptor and farnesoid X receptor ligands differentially regulate sebaceous differentiation in human sebaceous gland organ cultures in vitro.

BACKGROUND: Nuclear hormone receptors are important in the regulation of epidermal differentiation and have been implicated in lipid metabolism. In particular, there is evidence suggesting that the activation of peroxisome proliferator-activated receptors (PPARs) is an important factor in the regulation of sebocyte lipogenesis. OBJECTIVES: To determine the role of PPARs, farnesoid X receptor (FXR) and other orphan nuclear hormone receptors in sebaceous gland function in vitro by investigating the biochemical effects of appropriate ligands, and by establishing the RNA and protein expression patterns of a number of nuclear receptors in sebaceous glands ex vivo. METHODS: Human chest sebaceous glands were maintained in vitro as freshly isolated and as 7-day cultured whole organs. We then studied the effects of appropriate ligands on the glandular rates of lipogenesis and DNA synthesis, as well as determining the mRNA (reverse transcription-polymerase chain reaction) and protein expression patterns (immunohistochemistry/immunoblotting) of the nuclear hormone receptors of interest. RESULTS: PPAR ligands, but not FXR ligands, inhibited sebaceous lipogenesis, in particular the PPARalpha ligands LY 171883 and WY 14643, and the PPARgamma ligands BRL 49653 and 15-deoxy-Delta-12,14-prostaglandin J(2). We detected RNA expression of PPARalpha, PPARbeta, PPARgamma, retinoid X receptor alpha, liver X receptor alpha (LXRalpha) and pregnane X receptor but not FXR in freshly isolated and 7-day maintained sebaceous glands. PPARalpha, PPARbeta, PPARgamma and LXRalpha protein were detected in nuclear extracts of sebaceous glands. CONCLUSIONS: We conclude that activation of nuclear hormone receptors, in particular activation of PPARalpha and PPARgamma, can regulate lipogenesis in human sebaceous glands. As suppression of sebum secretion is associated with reduced acne activity, the nuclear hormone receptors involved may open new avenues in the development of novel acne treatments.

Human sebaceous glands engage in aerobic glycolysis and glutaminolysis.

BACKGROUND: The skin and its appendages support aerobic glycolytic and glutaminolytic metabolism. Their major fuels are glucose and glutamine, which are, however, largely catabolized anaerobically. OBJECTIVES: For the human sebaceous gland it has been reported that glucose, lactate and acetate provide good lipogenic substrates but that glutamine does not. Therefore, we have investigated the intermediary metabolism in vitro of freshly isolated human sebaceous glands to determine if their metabolism of glutamine is anomalous relative to the rest of the skin. METHODS: Glycolytic rate, glucose and glutamine oxidation, and glucose metabolism by the pentose phosphate pathway were determined in freshly isolated human chest sebaceous glands. Further, sebaceous intermediary metabolites were analysed using spectrophotometry and high-performance liquid chromatography. Moreover, glands were maintained in vitro as whole organs to investigate the effects of precursors and inhibitors of polyamine synthesis on rates and patterns of lipogenesis and DNA synthesis. RESULTS: We confirm that the human sebaceous gland is a glycolytic and glutaminolytic tissue. Glucose is mainly converted to lactate, with only 6% of glucose being oxidized to CO(2). Glutamine is largely converted to glutamate, alanine, serine, glycine, aspartate, threonine, lactate and ammonia, with only 12% being oxidized. We have also shown that exogenous glutamine is required for cellular proliferation and lipogenesis by human sebaceous glands. However, in its absence spermidine could fully restore rates of DNA synthesis and lipogenesis. CONCLUSIONS: Although glutamine is a poor substrate for sebaceous lipogenesis, this cannot be attributed to its lack of catabolism. We have shown that glutamine is an essential fuel, but that it can be replaced by exogenous spermidine. Therefore, we suggest that in sebocytes both glutamine and spermidine may act as essential purine and pyrimidine precursors.

Advances in sebaceous gland research: potential new approaches to acne management.

Sebaceous gland development and function is regulated by an expanding array of molecules including transcription factors, hormones, retinoids, growth factors, cytokines and nuclear hormone receptors. We have reviewed the literature to present the current understanding of sebaceous gland development and physiology, with particular emphasis on the control of the sebaceous gland and its implications for acne management. Interestingly, retinoids, cytokines and nuclear hormone receptors appear to be promising inhibitors of sebum synthesis, thus offering new approaches to acne management.

Modelling the remission of individual acne lesions in vitro.

BACKGROUND: Acne lesions spontaneously remit, but the mechanism of this remission has not been elaborated. It is known, however, that the remission is associated with a de-differentiation of sebocytes, causing a cessation of sebum secretion specific to that particular pilosebaceous unit. We have previously described the cytokines that will promote in vitro the lesions of acne. OBJECTIVES: To show that those same cytokines may also promote a de-differentiation of sebocytes analogous to that seen during remission of some lesions. METHODS: Human chest sebaceous glands were maintained in vitro as whole organs. We then chronicled the effects of the appropriate cytokines and growth factors on the glandular rates of (i) lipogenesis and (ii) DNA synthesis, as well as on (iii) glandular morphology, (iv) the expression patterns of the proliferation marker Ki-67, (v) keratinocyte-specific markers, and (vi) the sebocyte marker epithelial membrane antigen. RESULTS: We have shown that the same cytokines that promote comedogenesis (interleukin-1alpha), expression of infundibular intercellular adhesion molecule-1 and human leucocyte-associated antigen-DR (tumour necrosis factor-alpha and interferon-gamma), and infundibular disruption (epidermal growth factor/transforming growth factor-alpha) in human infundibula in vitro, will also inhibit sebaceous lipogenesis in vitro and will also induce, histologically, a de-differentiation of human sebocytes into a keratinocyte-like phenotype. CONCLUSIONS: These results confirm our hypothesis that the cytokines that induce the infundibular changes in acne may also inhibit the secretion of lipid from the sebaceous gland and thus, on diffusing down to the gland, contribute to the remission of the individual lesions. These findings help to explain the known natural history of the disease.