出版社：American Society for Biochemistry and Molecular Biology
摘要：Liver X receptor (LXR) nuclear receptors regulate the expressionof genes involved in whole body cholesterol trafficking, includingabsorption, excretion, catabolism, and cellular efflux, andpossess both anti-inflammatory and antidiabetic actions. Accordingly,LXR is considered an appealing drug target for multiple indications.Synthetic LXR agonists demonstrated inhibition of atherosclerosisprogression in murine genetic models; however, these and otherstudies indicated that their major undesired side effect isan increase of plasma and hepatic triglycerides. A significantimpediment to extrapolating results with LXR agonists from mouseto humans is the absence in mice of cholesteryl ester transferprotein, a known LXR target gene, and the upregulation in micebut not humans of cholesterol 7-hydroxylase. To better predictthe human response to LXR agonism, two synthetic LXR agonistswere examined in hamsters and cynomolgus monkeys. In contrastto previously published results in mice, neither LXR agonistincreased HDL-cholesterol in hamsters, and similar results wereobtained in cynomolgus monkeys. Importantly, in both species,LXR agonists increased LDL-cholesterol, an unfavorable effectnot apparent from earlier murine studies.
These results reveal additional problems associated with currentsynthetic LXR agonists and emphasize the importance of profilingcompounds in preclinical species with a more human-like LXRresponse and lipoprotein metabolism.Abbreviations: ABCG1, ATP binding cassette protein G1; apoE, apolipoprotein E; CETP, cholesteryl ester transfer protein; cyp7a, cholesterol 7-hydroxylase; HDL-C, high density lipoprotein-cholesterol; LXR, liver X receptor; SCD, steroyl coenzyme A desaturase; SREBP, sterol-regulatory element binding protein
Supplementary key words liver X receptor • low density lipoprotein • cholesteryl ester transfer protein • monkey • hamster • triglyceride • atherosclerosis
-hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies.
These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism.
Abbreviations: ABCG1, ATP binding cassette protein G1; apoE, apolipoprotein E; CETP, cholesteryl ester transfer protein; cyp7a, cholesterol 7
