CRH receptor (CRHR)1 and 2, whereas CRHR1 is more abundant and seems to regulate CRH activity (Zouboulis et al. 2002; Krause et al. 2007). Through binding to CRHR1, CRH and urocortin reduce sebocyte proliferation. CRH upregulates Δ^5–4 3β-hyroxysteroid dehydrogenase expression, synthesis of neutral lipids and interleukin(IL)6 and IL8 release.

Melanocortin [α-melanocyte stimulating hormone (α-MSH)]-1 and -5 receptors (MC1R and MC5R), which bind α-MSH and are located at the cellular surface of sebocytes. MC1R regulates inflammation in SZ95 sebocytes (Böhm et al. 2002) and exhibits a stronger expression in acne-involved sebaceous glands (Ganceviciene et al. 2007). The expression of MC5R is weaker than that of MC1R but has been shown to be a marker of human sebocyte differentiation, since it is expressed in differentiated, lipid-containing sebocytes, only (Zhang et al. 2006a).

µ-opiate receptors, which bind β-endorphin. β-endorphin stimulates lipogenesis and specifically increases the amount of C16:0, C16:1, C18:0, C18:1, and C18:2 fatty acids to an extent similar to linoleic acid in sebocytes (Böhm et al. 2004).

VPAC receptors, which bind vasoactive intestinal polypeptide, receptors for neuropeptide Y, and calcitonin gene-related peptide (Seiffert et al. 2000). Neuropeptide Y activates cytokine synthesis. The calcitonin gene-related peptide is often colocalized with substance P.

Cannabinoid receptors (CBR) 1 and 2 are expressed in SZ95 sebocytes and sebaceous glands (Ständer et al. 2005; Dobrosi et al. 2008). CBR1 was found in the differentiated sebocytes and CBR2 in the undifferentiated cells, whereas endocannabinoids influence sebocyte differentiation via CBR2.

Histamine 1 receptor, which binds with histamine and regulates squalene synthesis (Pelle et al. 2008). Antihistamines, ligands of histamine 1 receptor reduced squalene synthesis in SZ95 sebocytes.

The single-transmembrane domain receptors, insulin-like growth factor (IGF)-1 receptor, and epidermal growth factor (EGF) receptor that harbour intrinsic tyrosine kinase activity are expressed on SZ95 sebocyte cell surface.

IGF-1 receptor can be activated by IGF-1 and high concentrations of insulin (Makrantonaki et al. 2006). It amplifies lipid accumulation in SZ95 sebocytes in a dose-dependent manner. The activation of the IGF-1 receptor induced lipogenesis in SEB-1 sebocytes by sterol response element-binding protein-dependent and independent pathways (Smith et al. 2006). IGF-1 also stimulates proliferation and differentiation of rat preputial gland cells, which resemble sebocytes, especially in combination with growth hormone (GH; Deplewski and Rosenfield 1999).

EGF receptor was shown to be expressed in human sebocytes (Nanney et al. 1984; Takata et al. 2012). Its inhibition in SZ95 sebocytes led to upregulation of adipophilin and MC5R expression levels, which are differentiation markers for human sebocytes, and enhanced proinflammatory signaling by induction of IL6, IL8, and tumor necrosis factor-α release. Current data indicate that EGF may play a multimodal role on sebaceous gland cell proliferation, differentiation, lipogenesis, and inflammatory signaling (Zouboulis 2013).

Activation of GH receptor, which does not possess intrinsic tyrosine kinase activity but appear to function through interaction with soluble transducer molecules, in SZ95 sebocytes, stimulates sebocyte differentiation and augments the effect of 5α-dihydrotestosterone (DHT) on sebum synthesis (Zouboulis et al. 2002; Makrantonaki et al. 2006).

Human sebocytes exhibit the highest AR density among human skin cells. AR down regulation reduces sebocyte proliferation (Fimmel et al. 2007). Five intracellular enzymes—all of them expressed in sebocytes (Fritsch et al. 2001)—are involved in activation and inactivation of androgens before binding to AR. Dehydroepiandrosterone (DHEA) sulfate is metabolized by the steroid sulfatase to DHEA. DHEA and androstosterone are converted to testosterone and later to DHT by 5α-reductase (Fritsch et al. 2001; Chen et al. 1998). Sebocyte studies of Akamatsu et al. and Zouboulis et al. showed a dose-dependent induction of sebocyte proliferation by testosterone treatment (Akamatsu et al. 1993) and no effect on lipid stimulation (Zouboulis et al. 1999). Investigations by Rosenfield et al. and Makrantonaki et al. proved that the effect of androgens on sebaceous lipids is mediated by peroxisome proliferator-activated receptor (PPAR) ligands (Rosenfield et al. 1998; Makrantonaki and Zouboulis 2007).

PR was found in nuclei of basal sebocytes of sebaceous glands (Pelletier and Ren 2004). The thyroid receptors, estrogen receptors (ER; α- and β-isotypes; Pelletier and Ren 2004; Thornton et al. 2006; Thornton et al. 2003), retinoic acid receptors (RAR; isotypes α and γ), and retinoid X receptors (RXR; isotypes α, β, γ; Reichrath et al. 1997; Tsukada et al. 2000), vitamin D receptor (VDR; Reichrath et al. 2000), PPAR (Makrantonaki and Zouboulis 2007; Schmuth et al. 2005; Alestas et al. 2006), and liver X receptors (LXR; -α and -β isotypes; Russell et al. 2007; Hong et al. 2008) are expressed in human sebocytes.

ER-β is expressed in basal and partially differentiated sebocytes. ER-α is expressed in basal and early differentiated sebocytes. One of the natural estrogens, estradiol, is created by oxidative reduction of 4-androstene-3,17-dione. Treatment of sebocytes with 17β-estradiol showed an effect on polar lipid production but no stimulating effect on neutral lipids (Makrantonaki et al. 2008). Other previous in vitro data indicated that estrogens may have an influence on the biological activity of sebaceous glands (Guy et al. 1996).

RARα and γ and RXRα are the predominant retinoid receptors in human sebocytes. RAR regulates cell proliferation (Tsukada et al. 2000). The natural ligands for RAR and RXR are all-tans-retinoic acid (RA) and 9-cis RA. 13-cis RA inhibits proliferation of SZ95 sebocytes, whereas it was found to be metabolized intracellularly to its isoform and RAR ligand all-tans-RA. RXR agonists (rexinoids) are stimulating sebocyte differentiation and proliferation. Rexinoids in combination with specific PPAR agonists, such WY 14643, troglitazone and cabaprostacycline, affected differentiation and growth in cultured primary sebocyte-like rat preputial cells (Kim et al. 2001).

SZ95 sebocytes were found to express vitamin D-25-hydroxylase, 25-hydroxyvitamin D-1α-hydroxylase, and 1,25-dihydroxyvitamin D-24-hydroxylase (24OHase; Krämer et al. 2009). Vitamin D₃ induces time- and dose-dependent modulation of cell proliferation, cell cycle regulation, lipid content, and IL6 and IL8 secretion by cultured sebocytes. RNA expression of VDR and 24OHase was upregulated along with vitamin D₃ treatment.

PPARα and γ are the predominant PPAR subtypes in human sebocytes (Alestas et al. 2006). PPAR is present in mitochondria, peroxisomes and microsomes of sebocytes, and regulate multiple lipid metabolic genes. Sebaceous lipogenesis is maximally induced by androgens and PPAR ligands (Makrantonaki and Zouboulis 2007).

SZ95 sebocytes express LXRα and β receptors at the mRNA and protein levels. The application of natural 22(R)-hydroxycholesterol or synthetic ligands significantly inhibited sebocyte proliferation and increased lipogenesis. The expression of known LXR targets, such as fatty acid synthase and SREBP1, was induced by the synthetic LXR ligand TO901317, which also decreased the expression of cyclooxygenase 2 and inducible nitric oxide synthase that was induced by lipopolysaccharide treatment (Hong et al. 2008).