Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

Abstract

Nuclear receptors have an integral role in cellular processes, translating metabolic, hormonal and nutritional signals to changes in gene expression. Liver X receptor (LXR) and farnesoid X receptor (FXR) form a heterodimer with retinoid X receptor (RXR) and mediate changes in gene expression following activation by their natural ligands, oxysterols and bile acids, respectively. LXRs regulate whole-body cholesterol homeostasis by controlling the uptake, transport and excretion of cholesterol in a tissue-selective manner. In addition to having effects on cholesterol regulation, LXR activation has been shown to mediate changes in lipid and carbohydrate metabolism in the liver and in extra-hepatic tissues such as adipose, skeletal muscle and the pancreas. FXR is a central regulator of bile acid homeostasis, controlling key steps in the production and enterohepatic circulation of bile acids. FXR mediates its effects on bile acid metabolism via direct induction of target genes and by indirect repression via induction of small heterodimer partner (SHP). Recent studies have demonstrated an additional role for FXR in the regulation of lipid and glucose metabolism. Alterations to the above-mentioned pathways are associated with obesity, diabetes and atherosclerosis. LXR and FXR act on mulitple pathways involved in these metabolic diseases, making these nuclear receptors attractive targets for pharmaceutical intervention on multiple levels.