Understanding the molecular mechanisms behind lipid homeostasis: the role of apoE and hepatic ACAT 2 in atherogenesis

The general aim of this work was to investigate the molecular mechanisms involved in lipoprotein metabolism and lipid homeostasis trying to further clarify the role played by apolipoprotein E and hepatic Acyl-conzyme A:cholesterol acyltransferase 2 (ACAT2). ApoE-/- mice provide the the most useful model to study hyperlipidemia and atherosclerosis. In the first part of this work we assessed whether the expression of apoE may have a significant impact on the atheroprotective process of reverse cholesterol transport (RCT) in mice. In the second part of this work we focused attention on ACAT2 down-regulation by antisense oligonucleotide therapy (ASO), a new potential strategy to retard atherosclerosis. We investigated whether a decreased hepatic ACAT2 activity may increase HDL synthesis and affect triglyceride and cholesterol metabolism by activation of the LXR pathway. From RCT study we concluded that apoE is essential for functional RCT. The use of anti-sense oligonucleotide targeted to hepatic ACAT2 revealed a new pathway by which the liver contributes to HDL metabolism and identify ACAT2 as an important intracellular player in the determination of cholesterol fluxes either into apoB-containing lipoprotein secretion or into apoA-I.