title: Mechanisms of the triglyceride- and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients.
abstract: In humans, the precise mechanisms of the hypolipidemic action of fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, remain unclear. To gain insight on these mechanisms, we measured plasma lipids levels, lipids synthesis (hepatic de novo lipogenesis and cholesterol synthesis), and mRNA concentrations in circulating mononuclear cells (RT-PCR) of hydroxymethylglutaryl (HMG)-CoA reductase, LDL receptor, LDL receptor- related protein (LRP), scavenger receptor class B type I (SR-BI), ABCAI, and liver X receptor (LXR)-alpha in 10 control subjects and 9 hyperlipidemic type 2 diabetic patients. Type 2 diabetic subjects were studied before and after 4 months of fenofibrate administration. Fenofibrate decreased plasma triglycerides (P < 0.01) and total cholesterol (P < 0.05) concentrations and slightly increased HDL cholesterol (P < 0.05). Hepatic lipogenesis, largely enhanced in diabetic subjects (16.1 +/- 2.1 vs. 7.5 +/- 1.6% in control subjects, P < 0.01), was decreased by fenofibrate (9.8 +/- 1.5%, P < 0.01). Fractional cholesterol synthesis was normal in diabetic subjects (3.5 +/- 0.4 vs. 3.3 +/- 0.5% in control subjects) and was unchanged by fenofibrate (3.5 +/- 0.5%). Absolute cholesterol synthesis was, however, increased in diabetic subjects before and after fenofibrate (P < 0.05 vs. control subjects). HMG-CoA reductase, LDL receptor, LRP, and SR-BI mRNA concentrations were not different in type 2 diabetic and control subjects and were unchanged by fenofibrate. LXR-alpha mRNA levels were increased (P < 0.05) by fenofibrate. ABCAI mRNA concentrations, which were decreased in diabetic subjects (P < 0.05) before fenofibrate, were increased (P < 0.05) by fenofibrate to values comparable to those of control subjects. The plasma triglyceride-lowering effect of fenofibrate is explained in part by a decrease in hepatic lipogenesis, the moderate fall in total plasma cholesterol is not explained by a reduction of whole-body cholesterol synthesis, and the increase in LXR-alpha and ABCAI mRNA levels suggests that fenofibrate stimulated reverse cholesterol transport.
authors.affiliation: INSERM U 499, Faculté RTH Laennec, Rue G Paradin, 69008 Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Forcheron
authors.forename: Ana
authors.initials: A
authors.lastname: Cachefo
authors.forename: Sylvie
authors.initials: S
authors.lastname: Thevenon
authors.forename: Claudie
authors.initials: C
authors.lastname: Pinteur
authors.forename: Michel
authors.initials: M
authors.lastname: Beylot
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D002784:Cholesterol / Q000097:blood*; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D006728:Hormones / Q000097:blood; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000097:blood / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D014280:Triglycerides / Q000097:blood*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D006728:Hormones; D000960:Hypolipidemic Agents; D008055:Lipids; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D014280:Triglycerides; D002784:Cholesterol; D011345:Fenofibrate