New prospects for lipid-lowering drugs

The advent of 3-hydroxy-methylglutaryl Co-enzyme A (HMG-CoA) reductase inhibitors has dramatically improved the treatment of dyslipidaemia and the prevention of atherosclerosis over the past 10 years. Similar but less marked benefit had previously been demonstrated for fibrates and bile acid sequestrants, which were first introduced over 30 years ago and are still in use. The discovery that fibrates are ligands for peroxisome proliferator activated receptors (PPARs) may lead to innovations in the future. However, most of the compounds now undergoing clinical trials are either HMG-CoA reductase inhibitors or bile acid sequestrants, which is indicative of the current emphasis on lowering low density lipoprotein (LDL) cholesterol. Drugs in an earlier stage of development include inhibitors of squalene synthase, which have yet to fulfil their initial promise, and of acylcholesterolacyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). Most of the earlier ACAT inhibitors were poorly absorbed, but compounds with better bioavailability hold considerable promise by virtue of their ability to inhibit ACAT in liver and arterial wall macrophages. MTP inhibitors have the potential to drastically reduce apolipoprotein B (apoB) secretion, but safety issues could negate this advantage. Thus, despite the impact of statins, the development of new lipid-modulating drugs continues to be a dynamic field of research.     

Liver X receptor modulators: Effects on lipid metabolism and potential use in the treatment of atherosclerosis

Liver X receptors (LXRs) are nuclear receptors that play a crucial role in regulating the expression of genes involved in lipid metabolism. Ligand activation of LXRs improves cholesterol homeostasis via multiple coordinated effects, and this function is likely to explain in part the protective effects of LXR activation on atherosclerosis reported in animal models. However, LXR activation may also induce undesirable side effects, such as lipogenesis and hypertriglyceridemia. This review discusses the potential to develop LXR modulators as therapeutic agents for atherosclerosis.     

Molecular modifications of cholesterol metabolism in the liver and the brain after chronic contamination with cesium 137

Twenty years after Chernobyl accident, the daily ingestion of foodstuff grown on contaminated grounds remains the main source for internal exposure to ionizing radiations, and primarily to cesium 137 (¹³⁷Cs). Though the effects of a long-term internal contamination with radionuclides are poorly documented, several non-cancerous pathologies have been described in this population. However, lipid metabolism was never investigated after chronic internal contamination although disturbances were observed in externally-exposed people. In this regard, we assessed the effects of a chronic ingestion of ¹³⁷Cs on hepatic and cerebral cholesterol metabolism. To mimic a chronically-exposed population, rats were given ¹³⁷Cs-supplemented water at a post-accidental dose (150 Bq/rat/day) during 9 months. The plasma profile, and brain and liver cholesterol concentrations were unchanged. A decrease of ACAT 2, Apo E, and LXR < alpha > mRNA levels was recorded in the liver. In the brain, a decrease of CYP27A1 and ACAT 1 gene expression was observed. These results clearly show that cholesterol metabolism is not disrupted by a chronic ingestion of ¹³⁷Cs, although several molecular alterations are observed. This work would be interestingly completed by studying the influence of ¹³⁷Cs in models likely more sensitive to contaminants, such as the fetus or individuals susceptible to a lipidic disease.