Augmentation of Lipogenesis by 15-Deoxy-Δ12,14-Prostaglandin J2 in Hamster Sebaceous Glands: Identification of Cytochrome P-450-mediated 15-Deoxy-Δ12,14-Prostaglandin J2 Production

Abstract

Prostaglandins (PGs) play important roles in the regulation of cutaneous cell functions under physiological and pathological conditions. In this study, we examined the involvement of PGs in sebocyte lipogenesis using non-steroidal anti-inflammatory drugs in vivo and in vitro. Hamster auricle sebocytes spontaneously differentiated to accumulate intracellular triacylglycerol (TG), under which the relative levels of 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2) to PGF(2alpha) and PGE2 increased. 15d-PGJ2 was found to augment the formation of lipid droplets, which was because of an increase of TG synthesis by diacylglycerol acyltransferase (DGAT). Furthermore, sebocytes constitutively produced cyclooxygenase 2 (COX-2), but not COX-1, in vivo and in vitro. When sebocytes were treated with COX inhibitors such as indomethacin, diclofenac, or NS-398, the production of PGF(2alpha) and PGE2 decreased. The production of 15d-PGJ2, however, was increased in these inhibitor-treated sebocytes. In addition, indomethacin, diclofenac, and NS-398 augmented the synthesis of TG along with the increase in DGAT activity. Similarly, topical administration of indomethacin to hamster auricles caused the development of sebaceous glands with the augmentation of sebum deposition in vivo. Furthermore, indomethacin and NS-398-augmented 15d-PGJ2 production and TG synthesis were suppressed by a non-selective cytochrome P-450 (CYP) inhibitor, SKF-525A. A ligand activator of peroxisome proliferation activating receptor gamma (PPARgamma), troglitazone-induced synthesis of TG, however, was not altered even in the presence of SKF-525A. These results suggest that 15d-PGJ2 is a crucial stimulator of sebocyte lipogenesis by augmenting DGAT-mediated synthesis of TG. In addition to the COX-2-dependent pathway of PG synthesis, our findings suggest a sebocyte-specific pathway of 15d-PGJ2 production by CYP, the activity of which may be evoked by inhibiting COX-2.

Triptolide suppresses ultraviolet B-enhanced sebum production by inhibiting the biosynthesis of triacylglycerol in hamster sebaceous glands in vivo and in vitro

“…Acyl CoA/DGAT activity in DHS treated with UVB and/or triptolide was measured using 1,2-dioleoyl glycerol (Cayman Chemical Co., Ann Arbor, MI, USA) and 14 C-palmitoyl-CoA (GE Healthcare Biosciences, Pittsburgh, PA, USA), as previously described (24).…”

An update on the role of the sebaceous gland in the pathogenesis of acne

“…In hamster sebocytes the expression of COX-2 has been also documented, 78 while the 15-desoxy-Δ 12,14 -PGJ 2 has been shown to induce the lipid synthesis in the cells. 79 Activation of the platelet-activating factor signalling pathway (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) which consists of a group of phosphocholines with various biological effects, including modulation of keratinocyte function and skin inflammation, can regulate the expression of inflammatory mediators, e.g., COX-2 and PGE 2 , as well as IL-8 in SZ95 sebocytes. 80 Transgenic keratin 5 promoter driven overexpression of COX-2 in the basal compartment of the epidermis of the mouse and increased PGE 2 levels have been documented to cause sebaceous gland hyperplasia and overshooting sebum production pointing to a role of COX-2-mediated PGE 2 synthesis in this process.…”

Suppression of Sebum Production and Accumulation by <i>β</i>-Cryptoxanthin Due to the Inhibition of the Expression of Diacylglycerol Acyltransferase-1 and Perilipin in Hamster Sebocytes

“…Hamster sebocytes (2.4 × 10 4 cells/cm 2 ) [32] were plated onto 96-well multiplates, 35-mm or 100-mm diameter culture dishes (Becton Dickinson, Tokyo, Japan) and then cultured for 24 h in DMEM/F12 (Invitrogen, Carlsbad, CA) supplemented with 6% heat-denatured fetal bovine serum (Nichirei Biosciences Inc., Tokyo, Japan), 2% human serum (C-C Biotech Co., Valley Center, CA), 0.68 mM L-glutamine (Invitrogen), and recombinant human epidermal growth factor (10 nM) (Progen Biotechnik GmbH, Heidelberg, Germany) to achieve complete cell adhesion as previously described [6,18]. The hamster sebocytes were treated every two days for up to 8 days with or without β-CRX (purity ≥ 95%; Shikoku Yashima Pure Chemicals, Tokushima, Japan) (Figure 1) or 13-cisRA (Sigma Chemical, St. Louis, MO) in the presence or absence of a sebocyte-differentiation inducer, insulin (10 nM) (Sigma Chemical) [12] in DMEM/F12 supplemented with heat-denatured fetal bovine serum, human serum, and L-glutamine.…”

“…Sebum production in acne lesions has been reported to be increased by 5α-dihydrotestosterone, insulin, insulin-like growth factor 1, and prostaglandins [5][6][7][8][9]. In addition, the biosynthesis of sebum components such as triacylglycerols (TGs) and sapienic acids is regulated by diacylglycerol acyltransferase (DGAT), a rate-limiting enzyme of TG synthesis [6,10], and ∆6 desaturase (FADS2) [11], respectively, in human and hamster sebocytes.…”

“…In addition, the biosynthesis of sebum components such as triacylglycerols (TGs) and sapienic acids is regulated by diacylglycerol acyltransferase (DGAT), a rate-limiting enzyme of TG synthesis [6,10], and ∆6 desaturase (FADS2) [11], respectively, in human and hamster sebocytes. Furthermore, we have previously reported that the production of perilipin (PLIN), a lipid storage droplet protein, is augmented in differentiated hamster sebocytes and localized on the surface of intracellular lipid droplets, indicating that perilipin is a differentiation marker in hamster sebocytes [12].…”