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

Key Points 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. Nuclear receptors integrate hormonal and nutritional signals, resulting in changes to key metabolic pathways within the body. The liver X receptor (LXR) and the farnesoid X receptor (FXR), which are activated by oxysterols and bile acids, respectively, have essential roles in the regulation of cholesterol and bile acid metabolism but are also key integrators of sterol, fatty acid and glucose metabolism. Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid meta