Mechanisms of the Triglyceride- and Cholesterol-Lowering Effect of Fenofibrate in Hyperlipidemic Type 2 Diabetic Patients

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 12; pp. 3486 - 3491
• Main Authors: Forcheron, Fabien, Cachefo, Ana, Thevenon, Sylvie, Pinteur, Claudie, Beylot, Michel
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.12.2002
• Subjects: Adult; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; Cholesterol - blood; Diabetes Mellitus, Type 2 - complications; DNA-Binding Proteins; Drug therapy; Female; Fenofibrate - therapeutic use; Hormones - blood; Humans; Hyperlipidemias - blood; Hyperlipidemias - drug therapy; Hyperlipidemias - etiology; Hypoglycemic agents; Hypolipidemic Agents - therapeutic use; Lipids - biosynthesis; Liver - metabolism; Liver X Receptors; Male; Middle Aged; Orphan Nuclear Receptors; Physiological aspects; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid - genetics; Receptors, Thyroid Hormone - genetics; RNA, Messenger - blood; RNA, Messenger - metabolism; Triglycerides - blood; Type 2 diabetes
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.12.3486

Mechanisms of the Triglyceride- and Cholesterol-Lowering Effect of Fenofibrate in Hyperlipidemic Type 2 Diabetic Patients Fabien Forcheron 1 , Ana Cachefo 1 , Sylvie Thevenon 1 , Claudie Pinteur 1 and Michel Beylot 1 2 1 INSERM U 499, Faculté RTH Laennec, Lyon, France 2 Research Center for Human Nutrition, Hôpital Ed. Herriot, Lyon, France Abstract In humans, the precise mechanisms of the hypolipidemic action of fenofibrate, a peroxisome proliferator-activated receptor-α 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)-α 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-α 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-α and ABCAI mRNA levels suggests that fenofibrate stimulated reverse cholesterol transport. Footnotes Address correspondence and reprint requests to M. Beylot, MD, INSERM U 499, faculté RTH Laennec, Rue G Paradin, 69008 Lyon, France. E-mail: beylot{at}laennec.univ-lyon1.fr . Received for publication 4 June 2002 and accepted in revised form 6 September 2002. ASR, absolute synthetic rate; DNL, de novo lipogenesis; FFA, free fatty acid; FSR, fractional synthetic rate; HMG, hydroxymethylglutaryl; LPL, lipoprotein lipase; LRP, LDL receptor-related protein; LXR, liver X receptor; PPAR, peroxisome proliferator-activated receptor; SR-BI, scavenger receptor class B type I. DIABETES