Gene Expression Analyses in Cynomolgus Monkeys Provides Mechanistic Insight into High Density Lipoprotein-Cholesterol Reduction by Androgens in Primates.

@article{citeulike:2229822, abstract = {Androgens increase muscle mass, decrease fat mass, and reduce high density lipoprotein cholesterol (HDL-C), 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 days 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 LDL cholesterol without altering other lipoprotein particles. Liver and visceral fat biopsies taken before and after DHT treatment for 1 or 14 days 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 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 insulin-like growth factor I and beta-catenin were induced, as were extracellular matrix, cell adhesion, and cytoskeletal components, while there was consistent down-regulation of genes involved in triacylglycerol metabolism. Interestingly, cholesterol ester transfer protein (CETP) RNA was induced rapidly in monkey adipose tissue, while its inhibitor apolipoprotein CI (APOCI) 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-C reduction.}, address = {From the Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, Department of Molecular Profiling, Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck \& Co., Inc., Department of Laboratory Animal Resources, Merck Research Laboratories and Department of Biometrics, Merck Research Laboratories, West Point PA, 19486.}, author = {Nantermet, Pascale and Harada, Shun-Ichi I. and Liu, Yuan and Cheng, Spring and Johnson, Colena and Yu, Yuanjiang and Kimmel, Donald and Holder, Daniel and Hodor, Paul and Phillips, Robert and Ray, William J J. }, citeulike-article-id = {2229822}, doi = {http://dx.doi.org/10.1210/en.2007-1151}, issn = {0013-7227}, journal = {Endocrinology}, keywords = {adipose, dht, expression, gene, hdl, monkey}, month = {January}, posted-at = {2008-01-14 10:30:22}, priority = {2}, title = {Gene Expression Analyses in Cynomolgus Monkeys Provides Mechanistic Insight into High Density Lipoprotein-Cholesterol Reduction by Androgens in Primates.}, url = {http://dx.doi.org/10.1210/en.2007-1151}, year = {2008} }

TY - JOUR ID - citeulike:2229822 L3 - citeulike-article-id:2229822 N2 - Androgens increase muscle mass, decrease fat mass, and reduce high density lipoprotein cholesterol (HDL-C), 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 days 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 LDL cholesterol without altering other lipoprotein particles. Liver and visceral fat biopsies taken before and after DHT treatment for 1 or 14 days 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 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 insulin-like growth factor I and beta-catenin were induced, as were extracellular matrix, cell adhesion, and cytoskeletal components, while there was consistent down-regulation of genes involved in triacylglycerol metabolism. Interestingly, cholesterol ester transfer protein (CETP) RNA was induced rapidly in monkey adipose tissue, while its inhibitor apolipoprotein CI (APOCI) 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-C reduction. JF - Endocrinology SN - 0013-7227 AD - From the Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, Department of Molecular Profiling, Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co., Inc., Department of Laboratory Animal Resources, Merck Research Laboratories and Department of Biometrics, Merck Research Laboratories, West Point PA, 19486. TI - Gene Expression Analyses in Cynomolgus Monkeys Provides Mechanistic Insight into High Density Lipoprotein-Cholesterol Reduction by Androgens in Primates. KW - adipose KW - dht KW - expression KW - gene KW - hdl KW - monkey AU - Nantermet, Pascale AU - Harada, Shun-Ichi AU - Liu, Yuan AU - Cheng, Spring AU - Johnson, Colena AU - Yu, Yuanjiang AU - Kimmel, Donald AU - Holder, Daniel AU - Hodor, Paul AU - Phillips, Robert AU - Ray, William J PY - 2008/01/10/ UR - http://dx.doi.org/10.1210/en.2007-1151 ER -