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Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview | Chapter 09 | Emerging Trends and Research in Biological Science Vol. 1

Fibrates are a class of medication that mainly lowers the blood triglyceride levels. They reduce the LDL and increase the levels of HDL C, in the blood. Clofibrate, the first member to be discovered                 in 1962, and introduced in USA in 1967, is withdrawn in 2002, due to unexplained hepatomegaly, hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early 1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk, progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular disease and diabetic retinopathy. Various clinical trials like VA-HIT trial (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial), FIELD trail. (The Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study, ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial) and  BIP (Bezafibrate Infarction Prevention Study)  trial and angiography trials, like LOCAT (Lopid Coronary Angiography Trial) and BECLAIT (Bezafibrate Coronary Atherosclerosis Intervention Trial) demonstrated the  beneficial effects of gemfibrozil and fenofibrate. Their mechanism of action remained obscure for three decades, ie till 1990s, when their mode of action was found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL) modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involving  the various  enzymes like LCAT (Lecithin-cholesterol acyl transferase) and CYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1)), transporters like ABC, CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP, OATP (Na+-dependent taurocholate transporter / organic anion transporters). These are the and nuclear factors like LXR, PPAR alfa etc. (liver orphan receptor α, and peroxisome proliferative nuclear factor), in relation to the mechanisms of action of fibrates are discussed. Areas of current interests in literature are briefed.

Author(s) Details

Dr. A. S. V. Prasad
Department of Internal Medicine, G.I.T.A.M Dental College, Rishikonda, Visakhapatnam, Andhra Pradesh, India.

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