Liver X receptor activation promotes macrophage-to-feces reverse cholesterol transport in a dyslipidemic hamster model.
Liver X receptor (LXR) activation promotes reverse cholesterol transport (RCT) in rodents but has major side effects (increased triglycerides and LDL-cholesterol levels) in species expressing cholesteryl ester transfer protein (CETP). In the face of dyslipidemia, it remains unclear whether LXR activation stimulates RCT in CETP species. We therefore used a hamster model made dyslipidemic with a 0.3% cholesterol diet and treated with vehicle or LXR agonist GW3965 (30 mg/kg bid) over 10 days. To investigate RCT, radiolabeled (3)H-cholesterol macrophages or (3)H-cholesteryl oleate-HDL were then injected to measure plasma and feces radioactivity over 72 or 48 h, respectively. The cholesterol-enriched diet increased VLDL-triglycerides and total cholesterol levels in all lipoprotein fractions and strongly increased liver lipids. Overall, GW3965 failed to improve both dyslipidemia and liver steatosis. However, after (3)H-cholesterol labeled macrophage injection, GW3965 treatment significantly increased the (3)H-tracer appearance by 30% in plasma over 72 h, while fecal (3)H-cholesterol excretion increased by 156% (P < 0.001). After (3)H-cholesteryl oleate-HDL injection, GW3965 increased HDL-derived cholesterol fecal excretion by 64% (P < 0.01 vs. vehicle), while plasma fractional catabolic rate remained unchanged. Despite no beneficial effect on dyslipidemia, LXR activation promotes macrophage-to-feces RCT in dyslipidemic hamsters. These results emphasize the use of species with a more human-like lipoprotein metabolism for drug profiling.
Briand
François
F
Physiogenex SAS, Prologue Biotech, Rue Pierre et Marie Curie, B.P. 28262, Labège-Innopole, France. f.briand@physiogenex.com
Tréguier
Morgan
M
André
Agnès
A
Grillot
Didier
D
Issandou
Marc
M
Ouguerram
Khadija
K
Sulpice
Thierry
T
D000818:Animals; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D001596:Benzylamines / Q000494:pharmacology* / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000032:analysis; D001692:Biological Transport / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002460:Cell Line; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D007408:Intestinal Absorption / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D001565:Benzoates; D001596:Benzylamines; D001647:Bile Acids and Salts; C473027:GW 3965; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; C030104:lipoprotein cholesterol; D002784:Cholesterol