Testosterone metabolism to 5alpha-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes.
BACKGROUND
Despite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator-activated receptor (PPAR) ligands were suggested to be adequate candidates.


OBJECTIVE
The influence of testosterone and linoleic acid, a PPAR ligand, as single agents and in combination with of LY191704, a 5alpha-reductase type I inhibitor, was examined on 5alpha-dihydrotestosterone (5alpha-DHT) synthesis and lipid content in human SZ95 sebocytes.


METHODS
Cell proliferation and viability were measured by the 4-methylumbelliferyl heptanoate fluorescence assay and by the Boehringer Lactate Dehydrogenase Assay kit, respectively. 5alpha-DHT enzyme-linked immunosorbent assay was used for the detection of 5alpha-DHT synthesis in cell supernatants after treatment, whereas lipid production was documented by means of the Nile red lipid microassay and fluorescence microscopy.


RESULTS
Testosterone promoted 5alpha-DHT synthesis (P < 0.001), whereas linoleic acid increased sebaceous lipids (P < 0.001). The combination of testosterone and linoleic acid exhibited a synergistic effect on the synthesis of 5alpha-DHT (P < 0.01 vs. testosterone) and sebaceous lipids (P < 0.01 vs. linoleic acid). Furthermore, LY191704 reduced 5alpha-DHT and sebaceous lipid levels (P < 0.01 and P < 0.001 in comparison with testosterone/linoleic acid, respectively). Cell proliferation and viability remained unchanged under treatment with all compounds tested.


CONCLUSIONS
These data suggest a catalytic effect of PPAR ligands on cellular testosterone activation by 5alpha-reduction and the importance of the latter for the regulation of sebaceous lipids.
Makrantonaki
E
E
Laboratory of Biogerontology, Dermatopharmacology and Dermatoendocrinology, Institute of Clinical Pharmacology and Toxicology, Charité University Medicine Berlin, Berlin, Germany.
Zouboulis
C C
CC
D015068:17-Ketosteroids / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000732:Androstanols / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D008024:Ligands; D019787:Linoleic Acid / Q000378:metabolism / Q000494:pharmacology*; D008055:Lipids / Q000096:biosynthesis*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D012627:Sebaceous Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*
D015068:17-Ketosteroids; D058891:5-alpha Reductase Inhibitors; C418023:5-dihydrorubrosterone; D000732:Androstanols; D008024:Ligands; D008055:Lipids; D047492:Peroxisome Proliferator-Activated Receptors; D015363:Quinolones; C081531:8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinolin-3(2H)-one; D013739:Testosterone; D019787:Linoleic Acid