Androgens stimulate coordinated lipogenic gene expression in normal target tissues in vivo.
In prostate cancer cell lines in culture androgens cause a marked and coordinated upregulation of the expression of several lipogenic genes. Here, using castrated male Wistar rats as an experimental paradigm, we investigated whether coordinated androgen stimulation of lipogenic gene expression represents a more general physiological regulation in non-cancerous androgen-responsive cells as well. In typical target tissues for androgen action such as the ventral prostate and the lacrimal gland, androgen deprivation resulted in a marked reduction in the mRNA and protein levels of genes involved in fatty acid (fatty acid synthase and acetyl-CoA-carboxylase) and cholesterol synthesis (HMG-CoA-reductase and farnesyl diphosphate synthase). Readministration of testosterone immediately following orchidectomy restored the expression of all four genes. Substitution of testosterone by the non-aromatizable androgen dihydrotestosterone gave rise to comparable changes in the mRNA and protein levels of the lipogenic genes under investigation, confirming the involvement of the androgen receptor in the observed effects. In support of the coordinate nature of this regulation, androgen-induced upregulation of lipogenic gene expression is accompanied by an increase in the nuclear content of SREBP, a key lipogenic transcription factor. Taken together, these findings provide evidence for a coordinate regulation of lipogenic gene expression not only in prostate cancer cell lines in culture but also in non-cancerous androgen-responsive tissues in vivo.
Heemers
Hannelore
H
Faculty of Medicine, LEGENDO, Onderwijs en Navorsing 9, Gasthuisberg, K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Vanderhoydonc
Frank
F
Roskams
Tania
T
Shechter
Ishaiahu
I
Heyns
Walter
W
Verhoeven
Guido
G
Swinnen
Johannes V
JV
D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D051228:Geranyltranstransferase; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011467:Prostate / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D015854:Up-Regulation
D000728:Androgens; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D064429:Fatty Acid Synthases; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase