The mechanisms by which fibrates lower lipoprotein levels or raise HDL levels still remain unclear The effects on lipid and lipoprotein metabolism are mediated by activation of Peroxisome Proliferator -Activated Receptor a (PPARa) PPARs are a Subfamily of the unclear receptors There are 3 distinct type of PPARs -PPARa PPARB and PPARy each encoded by a separate gene and each with a distinct tissue distribution PPARa is highly expressed in liver kidney heart and muscle and in the cells of the areerial wall By activating PPARa fibrates influence the HDL metabolism After activation by fibrates activated PPAR heterodimerize with another nuclear receptor the retenoid X receptor and after the transcription of target genes after binding to specific peroxisome proliferator response elements (PPRE)
Activation of PPARa by fibrates induces Lipoprotein lipase (LPL) expression in the liver resulting in increased lipolysis An increase in lipolysis leads to an increase in pre -B-HDL which is a key acceptor of cholesterol from peripheral cells during the process of reverse cholesterol transport Scavenger receptor class B type 1 (SR-B1) and its human homologue (CLA-1) are cell surface receptors that bind HDL with high affinity and mediate the selective uptake of cholesteryl ester from HDL in liver and steroidogenic tissues Fibrates increase the synthesis of HDL by acting on genes encoding for Apo Al Apo AII and LPL In addition by increasing expression of HDL receptor adenosine triphosphate binding cassette transporter -I and CLA/SR -BI they influence reverse cholesterol transport by accelerating the cholesterol efflux Thus they enhance the HDL Protective effect and there fore lead to major clinical benefit
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