PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver.
11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol-cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11betaHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11betaHSD1 expression and activity after chronic treatment of wild-type mice with PPARalpha agonists, while 11betaHSD1 in the livers of PPARalpha knockout mice, or in mice treated for only 7 h with PPARalpha agonists, was unaltered. Our results are the first to show PPARalpha agonists can affect glucocorticoid metabolism in the liver by altering 11betaHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARalpha agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.
Hermanowski-Vosatka
A
A
Department of Atherosclerosis and Endocrinology, Department of Molecular Endocrinology, Department of Genomic Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey, USA. anne_vosatka@merck.com
Gerhold
D
D
Mundt
S S
SS
Loving
V A
VA
Lu
M
M
Chen
Y
Y
Elbrecht
A
A
Wu
M
M
Doebber
T
T
Kelly
L
L
Milot
D
D
Guo
Q
Q
Wang
P R
PR
Ippolito
M
M
Chao
Y S
YS
Wright
S D
SD
Thieringer
R
R
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005246:Feedback; D011345:Fenofibrate / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000201:enzymology*; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects
D004268:DNA-Binding Proteins; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D011345:Fenofibrate