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.     

Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor β (LXRβ) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXRβ activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXRβ and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element.     

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.