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Dihydrotestosterone induces SREBP-1 expression and lipogenesis through the phosphoinositide 3-kinase/Akt pathway in HaCaT cells
http://www.lipidworld.com/content/11/1/156Abstract
Background
The purpose of this study was to investigate the effects and mechanisms of dihydrotestosterone (DHT)-induced expression of sterol regulatory element binding protein-1 (SREBP-1), and the synthesis and secretion of lipids, in HaCaT cells. HaCaT cells were treated with DHT and either the phosphoinositide 3-kinase inhibitor LY294002 or the extracellular-signal-regulated kinase (ERK) inhibitor PD98059. Real time-PCR, Western blot, Oil Red staining and flow cytometry were employed to examine the mRNA and protein expressions of SREBP-1, the gene transcription of lipid synthesis, and lipid secretion in HaCaT cells.
Findings
We found that DHT upregulated mRNA and protein expressions of SREBP-1. DHT also significantly upregulated the transcription of lipid synthesis-related genes and increased lipid secretion, which can be inhibited by the addition of LY294002.
Conclusions
Collectively, these results indicate that DHT induces SREBP-1 expression and lipogenesis in HaCaT cells via activation of the phosphoinositide 3-kinase/Akt Pathway.
Introduction
Excessive secretion of sebum on skin is an important factor in various skin diseases, including acne and seborrheic dermatitis [1,2]. Besides sebaceous glands, keratinocytes are another important source of lipid on skin surface (2). Although the epidermis is certainly affected by steroid hormones, little is known about the effects of androgens on human keratinocytes. Previous studies demonstrated that in sebaceous glands androgens regulates the synthesis of sebum lipids through the sterol regulatory element-binding protein (SREBP) pathway [3]. Nevertheless, results of investigations on androgens receptor expression in keratinocytes are controversial: some groups have demonstrated that the androgens receptor is expressed in the epidermis [4], while others reported its absence [5]. Although nothing in the literature so far suggests that testosterone or its analog dihydrotestosterone (DHT) effect the growth of keratinocytes, we found that these hormones were associated with SREBP-1 expression in cells of the immortalized keratinocyte cell line HaCaT, which are quite similar to primary normal keratinocytes in steroid-metabolizing activity and responsiveness to steroid hormones [6].
The SREBP transcription factors bind sterol response elements, and three members of the SREBP family have been identified: SREBP-1a, SREBP-1c, and SREBP-2 [7]. In spite of the partial functional overlap between SREBP-1 and SREBP-2, SREBP-1 typically regulates genes in the fatty acid biosynthesis pathway, whereas SREBP-2 modulates the transcription of genes associated with cholesterol biosynthesis [8]. DHT has been reported to regulates SREBP-1 expression in various cell lines and organs [3,9,10]. Besides that, SREBP-1 was also found to be expressed in keratinocytes and played an important role in its lipid synthesis [11]. However, little is known of how DHT impacts the function of SREBP-1 in keratinocyte HaCaT cells. The aim of this study was to dissect the molecular signaling pathways by which DHT stimulation increases the mRNA and protein levels of SREBP-1 in HaCaT cells.
http://www.lipidworld.com/content/11/1/156Abstract
Background
The purpose of this study was to investigate the effects and mechanisms of dihydrotestosterone (DHT)-induced expression of sterol regulatory element binding protein-1 (SREBP-1), and the synthesis and secretion of lipids, in HaCaT cells. HaCaT cells were treated with DHT and either the phosphoinositide 3-kinase inhibitor LY294002 or the extracellular-signal-regulated kinase (ERK) inhibitor PD98059. Real time-PCR, Western blot, Oil Red staining and flow cytometry were employed to examine the mRNA and protein expressions of SREBP-1, the gene transcription of lipid synthesis, and lipid secretion in HaCaT cells.
Findings
We found that DHT upregulated mRNA and protein expressions of SREBP-1. DHT also significantly upregulated the transcription of lipid synthesis-related genes and increased lipid secretion, which can be inhibited by the addition of LY294002.
Conclusions
Collectively, these results indicate that DHT induces SREBP-1 expression and lipogenesis in HaCaT cells via activation of the phosphoinositide 3-kinase/Akt Pathway.
Introduction
Excessive secretion of sebum on skin is an important factor in various skin diseases, including acne and seborrheic dermatitis [1,2]. Besides sebaceous glands, keratinocytes are another important source of lipid on skin surface (2). Although the epidermis is certainly affected by steroid hormones, little is known about the effects of androgens on human keratinocytes. Previous studies demonstrated that in sebaceous glands androgens regulates the synthesis of sebum lipids through the sterol regulatory element-binding protein (SREBP) pathway [3]. Nevertheless, results of investigations on androgens receptor expression in keratinocytes are controversial: some groups have demonstrated that the androgens receptor is expressed in the epidermis [4], while others reported its absence [5]. Although nothing in the literature so far suggests that testosterone or its analog dihydrotestosterone (DHT) effect the growth of keratinocytes, we found that these hormones were associated with SREBP-1 expression in cells of the immortalized keratinocyte cell line HaCaT, which are quite similar to primary normal keratinocytes in steroid-metabolizing activity and responsiveness to steroid hormones [6].
The SREBP transcription factors bind sterol response elements, and three members of the SREBP family have been identified: SREBP-1a, SREBP-1c, and SREBP-2 [7]. In spite of the partial functional overlap between SREBP-1 and SREBP-2, SREBP-1 typically regulates genes in the fatty acid biosynthesis pathway, whereas SREBP-2 modulates the transcription of genes associated with cholesterol biosynthesis [8]. DHT has been reported to regulates SREBP-1 expression in various cell lines and organs [3,9,10]. Besides that, SREBP-1 was also found to be expressed in keratinocytes and played an important role in its lipid synthesis [11]. However, little is known of how DHT impacts the function of SREBP-1 in keratinocyte HaCaT cells. The aim of this study was to dissect the molecular signaling pathways by which DHT stimulation increases the mRNA and protein levels of SREBP-1 in HaCaT cells.