title: Fenofibrate reverses the decline in HDL cholesterol in mice overexpressing human phospholipid transfer protein.
abstract: In humans, fibrates are used to treat dyslipidemia, because these drugs lower plasma triglycerides and raise HDL cholesterol. Treatment with fibrates lowers plasma phospholipid transfer protein (PLTP) activity in humans, but increases PLTP activity in mice, without a consistent effect on HDL-cholesterol concentration. Earlier, we found that PLTP overexpression in transgenic mice results in decreased plasma HDL levels and increased diet-induced atherosclerosis. So it seems that the interplay between fibrates, PLTP and HDL is different in mice and man, which may be important for atherosclerosis development. In the present study, we measured the effects of fibrates on PLTP expression in cultured human hepatocytes and effects of fibrate treatment on human PLTP expression, plasma PLTP activity and HDL levels in human PLTP transgenic mice. Fibrate treatment did not influence PLTP mRNA levels in human hepatocytes. Hepatic human PLTP mRNA levels and PLTP activity were both moderately elevated by fenofibrate treatment in human PLTP transgenic mice. In wild-type mice, however, feeding fenofibrate resulted in a strong induction of PLTP mRNA in the liver and a more than 4-fold increase of plasma PLTP activity. Plasma triglycerides were reduced in all mice by 48% or more by fenofibrate treatment. HDL-cholesterol concentrations were substantially increased by fenofibrate in PLTP overexpressing mice (+72%), but unaffected in wild-type mice. We conclude that fenofibrate treatment reverses the HDL-lowering effect of PLTP overexpression in human PLTP transgenic mice.
authors.affiliation: Department of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lie
authors.forename: Inge M
authors.initials: IM
authors.lastname: Lankhuizen
authors.forename: Barbara
authors.initials: B
authors.lastname: Gross
authors.forename: Teus
authors.initials: T
authors.lastname: van Gent
authors.forename: Rien
authors.initials: R
authors.lastname: van Haperen
authors.forename: Leo
authors.initials: L
authors.lastname: Scheek
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
authors.forename: Arie
authors.initials: A
authors.lastname: van Tol
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood* / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger; D014280:Triglycerides; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D011345:Fenofibrate