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MOLECULAR DETERMINANTS OF THE REGULATION OF LXR ALPHA TRANSCRIPTIONAL ACTIVITY BY ACETYLATION IN MACROPHAGES

Final Report Summary - LXR ALPHA REGULATION (MOLECULAR DETERMINANTS OF THE REGULATION OF LXR ALPHA TRANSCRIPTIONAL ACTIVITY BY ACETYLATION IN MACROPHAGES)

Atherosclerosis is the hardening of the arteries that occurs when fat, cholesterol, and other substances build up in the walls of arteries and form structures called plaques or atherosclerotic lesions. Over time, these plaques can block the arteries and cause symptoms and problems such as heart attacks. Atherosclerosis is a major risk factor for cardiovascular or heart disease, which causes almost 50 per cent of deaths in Europe, and is reported to cost the EU economy about €169bn per year. In 2006 it was estimated that more than 17 million people worldwide die each year from heart disease. Thus cardiovascular disease is a growing problem for the developed world, which puts an even greater strain on healthcare systems. Currently, correction of abnormal cholesterol levels or dyslipidemias is a major goal in efforts to prevent cardiovascular disease. High levels of low density lipoprotein (LDL)-cholesterol has been shown to be associated with increase risk of heart disease. Supporting this, inhibitors of HMG-CoA reductase (the enzyme responsible for cholesterol synthesis) or statins are proved efficient LDL-cholesterol lowering drugs in reducing the risk of heart disease. However, these drugs only prevent approximately 35% of primary or secondary vascular events in large clinical trials indicating that risk factors other than high LDL-cholesterol are unaffected by statin therapy. In fact, most patients with coronary atherosclerosis do not have isolated high LDL-cholesterol concentrations but rather have low high density lipoprotein (HDL)-cholesterol or elevated triglycerides or both. This has triggered an intensive search for drugs that increase HDL formation and reverse cholesterol transport as additional strategies to treat and prevent cardiovascular risk.

Liver X receptors or LXRs are receptors that act as sensors for cellular cholesterol content (1). LXRs belong to a family of proteins called nuclear receptors, ie. transcription factors activated by ligands and in this way they control the expression of many genes encoding for proteins that are crucial to maintain cholesterol homeostasis. Activation of LXRs increases the level of HDL in blood, represses a number of inflammatory pathways (inflammation also being considered and important underlying factor in the pathogenesis of atherosclerosis). In this way LXR activation decreases the progression of atherosclerosis and the regression of established atherosclerotic lesions in animal models. Therefore in recent years, LXRs have been considered promising targets for drug development towards the management of human cardio-metabolic diseases such as atherosclerosis. Ideally, clinically relevant LXR activators would be tissue- and gene-specific modulators with favourable coronary anti-atherogenic and anti-inflammatory properties void of the less favourable hepatic effects (mainly the induction of lipid synthesis pathways that result in the elevation of triglyceride levels, which are a risk factor for heart disease). In light of the pivotal role LXR alpha plays in macrophage biology and atherosclerosis development, we believe that elucidating the signalling pathways modulating LXRα function will likely uncover novel points of intervention to be exploited in the development of alternative therapies against cardiovascular disease.