New Lipid-lowering Agents Acting on LDL Receptors

Abstract

The treatment of dyslipoproteinemia has proven a successful strategy in the prevention of cardiovascular diseases. The major target of hypolipidemic drugs is the reduction of low density lipoprotein cholesterol (LDL-C). HMG-CoA reductase inhibitors (HMGRI) effectively lower LDL-C by inhibiting the mevalonate pathway and enhancing the activity of the LDL receptor (LDL-R). Numerous clinical studies demonstrated convincingly, that the reduction of LDL-C lowers the incidence of cardiovascular events in primary and secondary prevention. Two new HMGRI, rosuvastatin and pitavastatin, have been evaluated in clinical trials. Both drugs demonstrated efficacy in lowering atherogenic lipoproteins. In addition to the reduction of LDL-C, they may have a higher potency to lower triacylglycerides (TG) and to increase HDL cholesterol (HDL-C) compared to currently available HMGRI. Other therapeutic strategies examined in experimental animals are the inhibition of squalene synthase, the first enzyme of the mevalonate pathway, which is specifically committed to cholesterol biosynthesis, and the direct up-regulation of LDL receptor activity. The latter compounds, the SCAP ligands, are the first members of a new class of hypolipidemic agents affecting the transcriptional regulation of genes involved in lipid metabolism. Recent treatment guidelines emphasise the importance of modifying lipid metabolism beyond lowering LDL-C, mainly by lowering TG and raising HDL-C. Although these actions are not primary targets of the compounds discussed here, it is interesting that drugs inducing the LDL-R usually also lower TG and, in the case of HMGRI, increase HDL-C.

Hepatitis C Virus Stimulates Low-Density Lipoprotein Receptor Expression To Facilitate Viral Propagation

“…It is well known that SREBPs are activated in low-sterol conditions, leading to the upregulation of lipid biosynthetic pathways and LDLR expression to promote internalization of cholesterol-rich lipoproteins from bloodstream, suggesting that the expression of LDLR on the cell surface of hepatocytes is inversely related to the cellular cholesterol concentration (14,19,20). This is the major mechanism through which statins work in reducing LDL-cholesterol levels in plasma by upregulating LDLR expression via inhibition of cholesterol synthesis (38). Interestingly, HCV activates SREBPs in normal physiologic conditions (30, 39) through a mechanism not completely elucidated, leading to the intracellular accumulation of lipids via enhanced synthesis and probably enhanced uptake by LDLR.…”

Characterization of rice bran wax policosanol and its nanoemulsion formulation

“…15 Other sources of policosanol include beeswax, wheat, sorghum, maize, rice, broccoli, spinach, alfalfa, and other cereal grains. The major components of policosanol mixture are octacosanol (66%), triacontanol (12%), and hexacosanol (7%).…”

Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine

“…One interest of combination therapy is to reach the goals recommended by the National Cholesterol Education Program Adult Treatment Panel III (11) and to limit the potential side effects observed with high doses of statins (12). Clearly, the discovery of new drugs that could be developed in combination with statins is still of interest, especially compounds targeting other lipid fractions, such as HDL cholesterol and triglycerides (TGs), or other risk factors, such as type II diabetes and hypertension.…”