title: Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters.
abstract: OBJECTIVE
  This study aimed to investigate whether cholesteryl ester transfer protein inhibition promotes in vivo reverse cholesterol transport in dyslipidemic hamsters.
  
  
  RESULTS
  In vivo reverse cholesterol transport was measured after an intravenous injection of (3)H-cholesteryl-oleate-labeled/oxidized low density lipoprotein particles ((3)H-oxLDL), which are rapidly cleared from plasma by liver-resident macrophages for further (3)H-tracer egress in plasma, high density lipoprotein (HDL), liver, and feces. A first set of hamsters made dyslipidemic with a high-fat and high-fructose diet was treated with vehicle or torcetrapib 30 mg/kg (TOR) over 2 weeks. Compared with vehicle, TOR increased apolipoprotein E-rich HDL levels and significantly increased (3)H-tracer appearance in HDL by 30% over 72 hours after (3)H-oxLDL injection. However, TOR did not change (3)H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E-rich HDL levels. After (3)H-oxLDL injection, TOR+berberine significantly increased (3)H-tracer appearance in fecal cholesterol by 109%.
  
  
  CONCLUSIONS
  Our data suggest that cholesteryl ester transfer protein inhibition alone does not stimulate reverse cholesterol transport in dyslipidemic hamsters and that additional effects mediated by the LDL-lowering drug berberine are required to upregulate this process.
authors.affiliation: Physiogenex SAS, Rue Pierre et Marie Curie, 31682 Labège, France. f.briand@physiogenex.com
authors.forename: François
authors.initials: F
authors.lastname: Briand
authors.forename: Quentin
authors.initials: Q
authors.lastname: Thieblemont
authors.forename: Elodie
authors.initials: E
authors.lastname: Muzotte
authors.forename: Thierry
authors.initials: T
authors.lastname: Sulpice
mesh_terms: D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D006224:Cricetinae; D004195:Disease Models, Animal; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy*; D005243:Feces / Q000737:chemistry; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011804:Quinolines; C099252:oxidized low density lipoprotein; D001599:Berberine; C014409:cholesteryl oleate; C483909:torcetrapib; D002784:Cholesterol