Fibrate - Mechanisms of Action

Mechanisms of Action

Evidence from studies in rodents and in humans is available to indicate five major mechanisms underlying the above-mentioned modulation of lipoprotein phenotypes by fibrates:

1. Induction of lipoprotein lipolysis: Increased triglyceride-rich lipoproteins (TRL) lipolysis could be a reflection of changes in intrinsic lipoprotein lipase (LPL) activity or increased accessibility of TRLs for lipolysis by LPL owing to a reduction of TRL apoC-III content.
2. Induction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production: In rodents, fibrates increase FA uptake and conversion to acyl-CoA by the liver owing to the induction of FA transporter protein and acyl-CoA synthetase activity. Induction of the ß-oxidation pathway with a concomitant decrease in FA synthesis by fibrates results in a lower availability of FAs for triglyceride synthesis, a process that is amplified by the inhibition of hormone-sensitive lipase in adipose tissue by fibrates.
3. Increased removal of LDL particles: Fibrate treatment results in the formation of LDL with a higher affinity for the LDL receptor, which are thus catabolized more rapidly.
4. Reduction in neutral lipid (cholesteryl ester and triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL.
5. Increase in HDL production and stimulation of reverse cholesterol transport: Fibrates increase the production of apoA-I and apoA-II in liver, which may contribute to the increase of plasma HDL concentrations and a more efficient reverse cholesterol transport.