11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice.
The enzyme 11beta-hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11beta-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11beta-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11beta-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11beta-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.
Hermanowski-Vosatka
Anne
A
Merck Research Laboratories, Merck and Company, Rahway, NJ 07065, USA. anne_vosatka@merck.com
Balkovec
James M
JM
Cheng
Kang
K
Chen
Howard Y
HY
Hernandez
Melba
M
Koo
Gloria C
GC
Le Grand
Cheryl B
CB
Li
Zhihua
Z
Metzger
Joseph M
JM
Mundt
Steven S
SS
Noonan
Heather
H
Nunes
Christian N
CN
Olson
Steven H
SH
Pikounis
Bill
B
Ren
Ning
N
Robertson
Nancy
N
Schaeffer
James M
JM
Shah
Kashmira
K
Springer
Martin S
MS
Strack
Alison M
AM
Strowski
Matthias
M
Wu
Kenneth
K
Wu
Tsueiju
T
Xiao
Jianying
J
Zhang
Bei B
BB
Wright
Samuel D
SD
Thieringer
Rolf
R
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001161:Arteriosclerosis / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D001381:Azepines / Q000008:administration & dosage*; D001786:Blood Glucose / Q000187:drug effects; D003348:Cortisone / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005227:Fatty Acids / Q000097:blood; D006854:Hydrocortisone; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D013577:Syndrome; D014230:Triazoles / Q000008:administration & dosage*; D014280:Triglycerides / Q000097:blood
C505014:3-(1-adamantyl)-6,7,8,9-tetrahydro-5H-(1,2,4)triazolo(4,3-a)azepine; D001381:Azepines; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007328:Insulin; D014230:Triazoles; D014280:Triglycerides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane; D003348:Cortisone; D006854:Hydrocortisone