Gene expression analyses in cynomolgus monkeys provides mechanistic insight into high-density lipoprotein-cholesterol reduction by androgens in primates.
Androgens increase muscle mass, decrease fat mass, and reduce high-density lipoprotein cholesterol (HDL), but the relationship between body composition, lipoprotein metabolism, and androgens has not been explained. Here we treated ovariectomized cynomolgus monkeys with 5alpha-dihydrotestosterone (DHT) or vehicle for 14 d and measured lipoprotein and triglycerides. Nuclear magnetic resonance analysis revealed that DHT dose-dependently reduced the cholesterol content of large HDL particles and decreased mean HDL particle size (P < 0.01) and also tended to lower low-density lipoprotein cholesterol without altering other lipoprotein particles. Liver and visceral fat biopsies taken before and after DHT treatment for 1 or 14 d were analyzed by genome-wide microarrays. In liver, DHT did not alter the expression of most genes involved in cholesterol synthesis or uptake but rapidly increased small heterodimer partner (SHP) RNA, along with concomitant repression of CYP7A1, a target of SHP transcriptional repression and the rate-limiting enzyme in bile acid synthesis. DHT regulation of SHP and CYP7A1 also occurs in rats, indicating a conserved mechanism. In adipose tissue, pathway analyses suggested coordinate regulation of adipogenesis, tissue remodeling, and lipid homeostasis. Genes encoding IGF-I and beta-catenin were induced, as were extracellular matrix, cell adhesion, and cytoskeletal components, whereas there was consistent down-regulation of genes involved in triacylglycerol metabolism. Interestingly, cholesterol ester transfer protein RNA was induced rapidly in monkey adipose tissue, whereas its inhibitor apolipoprotein CI was repressed. These data provide insight into the androgenic regulation of lipoprotein homeostasis and suggest that changes in adipose lipoprotein metabolism could contribute to HDL cholesterol reduction.
Nantermet
Pascale
P
Department of Alzheimer's Disease Research, Merck Research Laboratories, West Point, PA 19486, USA.
Harada
Shun-ichi
S
Liu
Yuan
Y
Cheng
Spring
S
Johnson
Colena
C
Yu
Yuanjiang
Y
Kimme
Donald
D
Holder
Daniel
D
Hodor
Paul
P
Phillips
Robert
R
Ray
William J
WJ
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000502:physiology; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D020411:Oligonucleotide Array Sequence Analysis; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D013196:Dihydrotestosterone; D002790:Cholesterol 7-alpha-Hydroxylase