Farnesoid X Receptor (NR1H4)

NRResource Content

FXR Poster (Actvation of FXR by bioactive lipids)

Pathways/Maps

Introduction

Farnesoid (or farnesol) X receptor (FXR) (or NR1H4) is a member of the same subclass of NR as LXR and , as well as the ecdysone receptor (ECR). FXR heterodimerizes to RXR and binds to DNA sequences consisting of an inverted repeat spaced by one nucleotide (IR-1) [1]. FXR is mainly expressed in the liver, gut, kidney, and adrenal cortex. FXR binds and is activated by several bile acids, including chenodeoxycholic acid, lithocholic acid (LCA), and deoxycholic acid. FXR received its name due to the fact that is activated by a large variety of endogenous isoprenoids, including farnesol. Other endogenous activators include all-trans-retinoic acid, and as mentioned above, fatty acids[2]. This nuclear receptor binds to AA, ALA and DHA with (Ki’s in the low M range ) but has little or no affinity for palmitic or stearic acid [2]. 

Role of FXR in Cardiovascular Disease. 

Several studies have shown that FXR activation by ligands has an anti-atherogenic effect in animal models [3-5]. For example, in apolipoprotein E-deficient (ApoE-/-) mice there was a decrease in aortic plaque formation when animals were fed the synthetic FXR ligand INT-74 [4]. FXR activation by natural and synthetic ligands attenuated IL-1beta, IL-6, and TNF-alpha gene induction in response to LPS, an effect reminiscent of what is commonly observed for PPAR activation. FXR reduces cholesterol uptake on macrophages by regulation of CD36 and ABCA1 expression. A target gene for FXR is the NR short heterodimer partner (SHP), a regulator of cholesterol metabolism in its own right. Both FXR and SHP are expressed in the aorta and macrophages and interest is growing in the potential for FXR ligands in the prevention and treatment of atherosclerotic lesions. 

References 

1. Francis GA, Fayard E, Picard F, Auwerx J: Nuclear receptors and the control of metabolism. Annu Rev Physiol 2003, 65:261-311. 
2. Zhao A, Yu J, Lew JL, Huang L, Wright SD, Cui J: Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. DNA Cell Biol 2004, 23(8):519-526. 
3. Evans MJ, Mahaney PE, Borges-Marcucci L, Lai K, Wang S, Krueger JA, Gardell SJ, Huard C, Martinez R, Vlasuk GP et al: A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol 2009, 296(3):G543-552. 
4. Mencarelli A, Renga B, Distrutti E, Fiorucci S: Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol 2009, 296(2):H272-281. 
5. Bishop-Bailey D: FXR as a novel therapeutic target for vascular disease. Drug News Perspect 2004, 17(8):499-504.