Augmentation of lipogenesis by 15-deoxy-Delta12,14-prostaglandin J2 in hamster sebaceous glands: identification of cytochrome P-450-mediated 15-deoxy-Delta12,14-prostaglandin J2 production.
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.
Iwata
Chikakazu
C
Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
Akimoto
Noriko
N
Sato
Takashi
T
Morokuma
Yuki
Y
Ito
Akira
A
D000818:Animals; D002454:Cell Differentiation; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D050155:Lipogenesis / Q000187:drug effects*; D011335:Proadifen / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D012627:Sebaceous Glands / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D014280:Triglycerides / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D052246:Cyclooxygenase 2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D014280:Triglycerides; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2