BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis

Abstract

During the last three years there have been a plethora of publications on the liver X-activated receptors (LXR ␣ , NR1H3, and LXR ␤ , NR1H2), the farnesoid X-activated receptor (FXR, NR1H4), and the pregnane X receptor (PXR, NR1I2) and the role these nuclear receptors play in controlling cholesterol, bile acid, lipoprotein and drug metabolism. The current interest in these nuclear receptors is high, in part, because they appear to be promising therapeutic targets for new drugs that have the potential to control lipid homeostasis. In this review we emphasize i ) the role of LXR in controlling many aspects of cholesterol and fatty acid metabolism, ii ) the expanded role of FXR in regulating genes that control not only bile acid metabolism but also lipoprotein metabolism, and iii ) the regulation of bile acid transport/metabolism in response to bile acid-activated

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

“…NR1H3, also known as LXRA, together with LXRB forms a subfamily of nuclear receptors that control transcriptional regulation of genes involved in lipid homeostasis, inflammation, and innate immunity (Joseph et al, 2003;Wang et al, 2002). The basic structure of these nuclear receptors consists of two activation domains (AF1 and AF2), a DNA binding domain, and an LBD responsible for dimerization (Edwards et al, 2002). The LXRA p.Arg415Gln mutation identified in MS families is located in a highly conserved amino acid of its LBD, which is not only conserved through speciation, but also present in the LBD of RXRs and LXRA nuclear receptor paralogs engaging in physical and functional interactions with RXRs (Figure 2) (Lefebvre et al, 2010).…”

“…Dimerization Analysis and Transcriptional Regulation of NR1H3 Target Genes NR1H3 encodes liver X receptor alpha (LXRA), which forms obligate heterodimer complexes with retinoid X receptors (RXRs) (Edwards et al, 2002). The p.Arg415Gln mutation identified in MS families is located on the surface of the heterodimerization interface on the ligand binding domain (LBD) (Figure 3A).…”

Cholesterol metabolism pathways – are the intermediates more important than the products?

“…including ABCA1, ABCG1 and the cholesterol carrier protein apolipoprotein E (APOE) [55,56]. In combination, the activation of LXR leads to removal of free cholesterol from cells by esterification, transport out of the cell by ABC transporters and its ultimate removal via apolipoproteins in the circulation.…”

Lipid Transport and Metabolism at the Blood-Brain Interface: Implications in Health and Disease

“…Several genes involved in cholesterol metabolism are regulated by liver X receptors (LXRs) (Schultz et al, 2000). LXRs act as cholesterol sensors and modify the expression of genes that regulate the transport, catabolism, and elimination of cholesterol, such as cholesterol ester transfer protein, lipoprotein lipase, and apolipoprotein E (APOE) (Edwards et al, 2002). The mRNA expression of LXRα and LXRβ has been detected in rat CP (Fujiyoshi et al, 2007), suggesting that they could be important for the BCSFB.…”