Lipid-lowering drugs

Abstract

Although a change in life-style is often the method of first choice for lipid lowering, lipid-lowering drugs, in general, help to control elevated levels of different forms of lipids in patients with hyperlipidemia. While one group of drugs, statins, lowers cholesterol, the other group, fibrates, is known to take care of fatty acids and triglycerides. In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia. As lipids are very critical for cardiovascular diseases, these drugs reduce fatal and nonfatal cardiovascular abnormalities in the general population. However, a number of recent studies indicate that apart from their lipid-lowering activities, statins and fibrates exhibit multiple functions to modulate intracellular signaling pathways, inhibit inflammation, suppress the production of reactive oxygen species, and modulate T cell activity. Therefore, nowadays, these drugs are being considered as possible therapeutics for several forms of human disorders including cancer, autoimmunity, inflammation, and neurodegeneration. Here I discuss these applications in the light of newly discovered modes of action of these drugs.

Figures

Figure 1

Schematic diagram depicting the various functions of statins. Statins suppress HMG-CoA reductase and thereby inhibit geranylation of Rac and farnesylation of Ras. Because both Rac and Ras are coupled to the transcription of proinflammatory molecules via MAP kinase pathways, statins reduce the expression of proinflammatory molecules. By suppressing geranylation of Rac, statins also attenuate NADPH oxidase-mediated production of reactive oxygen species (ROS). Phosphatidylinositol-3 (PI-3) kinase activates Akt, the kinase that has been shown to phosphorylate and stimulate endothelial nitric oxide synthase (eNOS). Mevalonate is capable of inhibiting PI-3 kinase, therefore, by reducing the concentration of mevalonate, statins up-regulate eNOS-derived production of NO resulting in vasorelaxation.

Figure 2

Lipid-lowering and anti-inflammatory functions of fibrate drugs. PPAR-α in the cytoplasm has been shown to bind heat-shock protein (HSP). However, the role of HSP is at present unclear. As has been shown in case of other nuclear hormone receptors, fibrates (F) may replace HSP. It has also not been demonstrated if ligand-bound PPAR-α enters into the nucleus. Within the nucleus, PPAR-α and RXR complex is bound to repressors, such as nuclear receptor co-repressor (NCoR), silencing mediator for retinoid and thyroid hormone receptor (SMRT) and histone deacetylase (HDAC). In the presence of ligand, NCoR, SMRT and HDAC are released from the complex followed by the recruitment of histone acetyltransferase (CBP/p300), steroid receptor co-activator (SRC), PPAR-binding protein (PBP), PPAR-interacting protein (PRIP), and PRIP-interacting protein with methyltransferase domain (PIMT). Subsequently, the whole active complex binds to peroxisome proliferator responsive element (PPRE) present in the promoter of peroxisomal fatty acid β-oxidizing enzymes. On the other hand, fibrates also inhibit the activation of AP-1 and NF-κB via PPAR-α. Although PPAR-α has been suggested to be involved in the up-regulation of IκBα, underlying mechanisms are unknown.