The role of hepatic nuclear receptors in systemic lipid homeostasis.

摘要

The nuclear receptor superfamily consists of ligand-activated transcription factors that regulate many genes important in physiological functions such as cellular differentiation as well as glucose and lipid metabolism. Nuclear receptors such as the farnesoid X receptor (FXR) and the liver X receptor function to maintain lipid homeostasis through regulation of genes encoding enzymes, receptors and transporters essential to lipid metabolism. A balance in the intracellular and systemic levels of lipids is crucial for the prevention of diseases such as cholestasis and atherosclerosis. The objectives of this thesis were to examine the role of FXR, a bile acid-activated nuclear receptor, in the regulation of lipid homeostasis and the development of atherosclerosis and to identify and characterize potential novel FXR targets. Through examination, via microarray, northern blot and quantitative PCR, of altered gene expression in various tissues of FXR-deficient mice (FXR-/-) versus wildtype mice, we discovered potential novel targets of this nuclear receptor. Regulatory mechanisms mediating expression of one of the genes altered in FXR-/- mice, apolipoprotein A-IV (apoA-IV), a protein involved in lipid transport and metabolism, were examined using a variety of mouse models and in vitro promoter assays. In addition, through the crossing of FXR-/- mice with a mouse model of atherosclerosis, the apoE-deficient mouse (apoE-/-), we were able to study the effect of deletion of this nuclear receptor on the development of atherosclerotic disease. Our results demonstrate that loss of FXR function leads to a disruption in lipid homeostasis through altered gene expression leading to decreased survival and a worsening of atherosclerosis in the apoE-/- background. In addition, our results describe a regulatory mechanism for apoA-IV involving the nuclear receptor hepatic nuclear factor-4alpha and a coactivator (peroxisome proliferator-activated receptor gamma coactivator-1alpha) that, in conjunction with glucocorticolds, induce apoA-IV in response to nutritional and metabolic stresses.