The over-expression of the LDL-receptor in the liver increases the clearance of circulating LDL, decreasing the LDL-cholesterol plasma levels.
The PPAR-α form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. These bio-molecular effects of fibrates are entirely due to their capacity to activate PPAR alpha and to induce the over expression of genes containing a PPRE in their promoter.
It is taken by mouth. This mechanism of action belongs to a class of drug called bile acid sequestrants.. Clofibrate was approved for use in 1967 in the United States. Fibric acid derivatives have been reported to decrease lipid levels to a moderate extent (15%–20%) and to reduce inflammation, as well as lowering proinflammatory activity in endothelial cells.Fibric acid derivatives (e.g., clofibrate, gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate) are employed clinically, but their mechanism of action is complex and debated.
This negligible increase in HDL is claimed to have caused a beneficial reduction in cardiac events.
These bio-molecular effects of fibrates are entirely due to their capacity to activate PPAR alpha and to induce the over expression of genes containing a PPRE in their promoter. Name must be less than 100 characters
The HDL cholesterol fell from 1.19 to 0.26 mmol/l. Fibrates increase high density-lipoprotein (HDL)-cholesterol by increasing apoA-I and apoA-II gene transcription.
Likewise, gemfibrozil-associated rhabdomyolysis occurs more often than that associated with fenofibrate.In the VA-HIT study gemfibrozil caused a 31% decrease in triglycerides, but only a 6% increase in HDL cholesterol compared with placebo. Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism Where views/opinions are expressed, they are those of the author(s) and not of Radcliffe Medical Media.Radcliffe Cardiology is part of Radcliffe Medical Media, an independent publisher and the Radcliffe Group Ltd. They increase the plasma triglyceride catabolism by inducing the lipoprotein lipase gene transcription and decreasing the apoC-III gene transcription. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. Likewise, a diabetic subject with triglycerides higher than 500mg/dl will need fibrate coverage irrespective of LDL levels. Although the word fibrate is suggestive of fiber, the fibrates do not act as GI lipid-absorbing fiber resins.
Recent evidence indicates that gemfibrozil causes increased levels of statins in the blood.In line with these results, overweight subjects (body mass index (BMI) >26) experienced more risk reduction from gemfibrozil compared with lean subjects (BMI <26), whereas the most striking risk reduction was produced by overweight or obese subjects (BMI >30) with high triglycerides and low HDL.The Veterans Administration HDL intervention trial (VA-HIT) evaluated the effect of gemfibrozil in CHD patients with type 2 diabetes or the metabolic syndrome and low HDL.However, the enthusiastic endorsement of fibrate therapy that could be derived from the VA-HIT results is partly tempered by the recent results of the Bezafibrate Infarction Prevention (BIP) Trial. Side effects include mild gastrointestinal discomfort, rash, and pruritus. However, statin-based interventions are unlikely to correct problems of triglycerides and HDL, whereas the use of fibrates has a stronger effect on the atherogenic dyslipidemia and might even produce significant LDL reduction in some patients.
It is not affiliated with or is an agent of, the Oxford Heart Centre, the John Radcliffe Hospital or the Oxford University Hospitals NHS Foundation Trust group. Mild aminotransferase elevations occur in 5% of the patients and return to normal after drug discontinuation.Triple-drug therapy with a statin, ezetimibe, and fenofibrate may help to obtain adequate reductions of both triglyceride levels and LDL-C without using very high statin doses. There have been several reviews published on PPAR-related transcription factors as well as the liver X receptor (LXR) transcription factor, both of which regulate lipid transport (One of the most ambitious new discovery efforts for treating dyslipidemia involves the LXR receptor. These stimulate peroxisome proliferator activated receptor alpha, which controls the expression of gene products that mediate the metabolism of TG and HDL. 2009;2009:706852. doi: 10.1155/2009/706852. Undesirable effects of LXR activation include increases in circulating triglycerides and hepatic steatosis. The primary mechanism is thought to be via interaction with peroxisome proliferator-activated receptor alpha (PPAR-α). The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes.
In the nucleus, this free NH2-terminal-SREBP-2 peptide binds to the SRE contained in the promoter of the gene of the LDL(B/E)-receptor and induces the transcription of this gene, and the over-expression of the LDL(B/E)-receptor in the cytoplasmic plasma membrane of hepatocytes.
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