INHIBITION OF HISTONE DEACETYLASES AS A NOVEL APPROACH FOR THE THERAPY OF MONOGENIC FAMILIAL HYPERCHOLESTEROLEMIA AND THE PREVENTION OF THE ASSOCIATED PREMATURE CORONARY ARTERY DISEASE

This application is aimed at identifying mechanisms of induction of the enzyme cholesterol 7 a -hydroxylase (CYP7A1), to develop new therapies for familial hypercholesterolemia, a monogenic disease characterized by extraordinarily elevated levels of cholesterol in the blood, which cause severe cardiovascular disease and premature myocardial infarction . The enzyme CYP7A1 controls the conversion of cholesterol to bile acids, a process that represents the major way to dispose cholesterol from the body. Our long-range goal is to design new treatments for familial hypercholesterolemia by stimulating this enzyme because it is crucial to reduce the risk of severe clinical outcome linked to this disorder. In preliminary studies, we discovered that administration of histone deacetylase inhibitors strongly decrease blood cholesterol by stimulating the gene encoding the enzyme CYPA71. Based on these extremely promising results, our hypothesis is that histone deacetylases silence the CYP7A1 gene. The rationale is, therefore, that the levels of blood cholesterol are correlated to the activity of enzyme CYP7A1 and that the induction of the gene encoding CYP7A1 lowers blood cholesterol. To accomplish the objective of this application we will pursue the following specific aims: 1) analysis of CYP7A1 repression and of 2) histone deacetylases recruited to CYP7A1 gene; 3) study of the effect of histone deacetylase inhibitors on blood cholesterol in an animal model of familial hypercholesterolemia. Our expectations are to better understand the mechanisms of repression of the gene encoding the enzyme cholesterol 7 a -hydroxylase and, most importantly, to accelerate the design of new and more effective therapies for familial hypercholesterolemia by exploiting the improved knowledge of these mechanisms .