A citrus polymethoxy flavonoid, nobiletin inhibits sebum production and sebocyte proliferation, and augments sebum excretion in hamsters.
Acne vulgaris is characterized by excess sebum production, and apart from all-trans retinoic acid (atRA) or 13-cis retinoic acid (13-cisRA), there are few effective agents for acne therapy that directly suppresses sebaceous lipogenesis. In this study, we demonstrated that topical application of a citrus polymethoxy flavonoid, nobiletin, to hamster auricles decreased skin surface triacylglycerols (TG) level and the size of sebaceous glands along with inhibition of diacylglycerol acyltransferase (DGAT)-dependent TG synthesis and sebocyte proliferation. The inhibitory actions were similar to that observed with atRA and 13-cisRA in hamster sebocytes. The antilipogenic and antiproliferative actions of nobiletin were also reproduced in UVB (5.4 kJ/m2)-irradiated hamsters, which showed aberrant enhancement of sebum accumulation and sebaceous enlargement. Furthermore, nobiletin, but not 13-cisRA, augmented sebum excretion along with increases in intracellular cAMP level, protein kinase A (PKA) activation, and apoptosis-independent phosphatidylserine (PS) externalization in cell membrane. These phenomena were reproduced by forskolin and inhibited by a PKA inhibitor, H-89. These results provide early evidence that nobiletin is an effective candidate for acne therapy through mechanisms that include the inhibition of DGAT-dependent TG synthesis and sebocyte proliferation, and the progression of apoptosis-independent and PS-externalization-dependent sebum excretion by PKA activation.
Sato
Takashi
T
Department of Biochemistry and Molecular Biology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan. satotak@ps.toyaku.ac.jp
Takahashi
Aiko
A
Kojima
Mika
M
Akimoto
Noriko
N
Yano
Masamichi
M
Ito
Akira
A
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D047309:Flavones / Q000627:therapeutic use*; D005419:Flavonoids / Q000627:therapeutic use*; D007546:Isoquinolines / Q000494:pharmacology; D008954:Models, Biological; D010718:Phosphatidylserines / Q000737:chemistry; D012629:Sebum / Q000166:cytology* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D000975:Antioxidants; D047309:Flavones; D005419:Flavonoids; D007546:Isoquinolines; D010718:Phosphatidylserines; D013449:Sulfonamides; D014280:Triglycerides; D014212:Tretinoin; C008661:nobiletin; D051048:Diacylglycerol O-Acyltransferase; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide