FXR an emerging therapeutic target for the treatment of atherosclerosis

Abstract

Atherosclerosis is the leading cause of illness and death. Therapeutic strategies aimed at reducing cholesterol plasma levels have shown efficacy in either reducing progression of atherosclerotic plaques and atherosclerosis-related mortality. The farnesoid-X-receptor (FXR) is a member of metabolic nuclear receptors (NRs) superfamily activated by bile acids. In entero-hepatic tissues, FXR functions as a bile acid sensor regulating bile acid synthesis, detoxification and excretion. In the liver FXR induces the expression of an atypical NR, the small heterodimer partner, which subsequently inhibits the activity of hepatocyte nuclear factor 4alpha repressing the transcription of cholesterol 7a-hydroxylase, the critical regulatory gene in bile acid synthesis. In the intestine FXR induces the release of fibroblast growth factor 15 (FGF15) (or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signalling to inhibit bile acid synthesis. In rodents, FXR activation decreases bile acid synthesis and lipogenesis and increases lipoprotein clearance, and regulates glucose homeostasis by reducing liver gluconeogenesis. FXR exerts counter-regulatory effects on macrophages, vascular smooth muscle cells and endothelial cells. FXR deficiency in mice results in a pro-atherogenetic lipoproteins profile and insulin resistance but FXR(-/-) mice fail to develop any detectable plaques on high-fat diet. Synthetic FXR agonists protect against development of aortic plaques formation in murine models characterized by pro-atherogenetic lipoprotein profile and accelerated atherosclerosis, but reduce HDL levels. Because human and mouse lipoprotein metabolism is modulated by different regulatory pathways the potential drawbacks of FXR ligands on HDL and bile acid synthesis need to addressed in relevant clinical settings.

Fig 1

Bile acids and hepatocyte cell signalling. (A.1): In the liver bile acids activate NR involved bile acid synthesis, uptake and detoxification. In addition to FXR, a master gene that inhibits their uptake and synthesis, bile acids activate PXR, CAR and VDR. These NRs regulate the expression/activity of phase I and II detoxification enzymes and the induction of canalicular and alternative basolateral transporters (A.2). (B). In the muscle cells (human) and brown adipose tissue (mouse) bile acids activate a cell membrane receptor, TGR-5 (M-BAR), involved in regulation of thermogenesis and basal energy expenditure.

Fig 3

Bile acids regulate their own synthesis. In hepatocytes bile acids accumulation activates FXR leading to an SHP and FGF-19 (human) dependent repression of CYP7A1 and CYP8B1, whereas PXR activation decreases directly the transduction of CYP7A1 and CYP8B1.

Fig 2

Molecular biology of FXR. (A) 3D structure of FXR. (http://www.rcsb.org/pdb/) in combination with an FXR synthetic agonist GW4064 (B) FXR molecular structure: includes a highly conserved DNA-binding domain in the N-terminal region and a moderately conserved Ligand Binding Domain (LBD) in the C-terminal region. The ligand-independent activation function-1 (AF-1) and ligand-dependent AF-2 are located in the N-terminal and C-terminal regions, respectively. (C) FXR molecular regulation: FXR bind DNA in correspondence to its FXREs. Coactivator and corepressor complexes are involved in FXR activation and repression, respectively. In the absence of a ligand, the FXR heterodimer associates with corepressor complexes, which recruit histone-deacetylase activities. Deacetylation of histone tails leads to chromatin compactation and transcriptional repression. Receptor activation causes the release of the corepressor complex and the AF-2-dependent recruitment of a coactivator complex that contains at least a p160 coactivator (such as SRC-1). These proteins possess histone-acetyltransferase activity that allows chromatin decompactation and gene activation. Multiple protein–protein interactions exist among the FXR and other coactivators such as PRMT-1 (protein arginine(R) methyl transferase-1) and CARM-1 (coactivator-associated arginine methyltransferase-1), inducing histone methylation and PGC-1α (ppar-γ coactivator-1α) and DRIP-205 (vitamin-D-receptor-interacting protein-205).

Fig 4

Metabolic and vascular effects of FXR. FXR heterodimerizes with RXR. The FXR/RXR heterodimer binds to FXR-responsive elements in the promoters of target genes. Following a ligand-induced activation, FXR induces the expression of genes encoding proteins involved in lipogenesis, lipoprotein clearance and glucose metabolism. In addition, FXR activation and sumoylation in macrophages stabilizes the nuclear co-repressor NCoR on NF-κB responsive element inhibiting the expression of inflammatory genes in macrophages, suppresses cell proliferation and migration and increases reverse cholesterol transport in VSMCs and endothelial cells. LDL-R, low-density lipoprotein receptor; VLDL, very low-density lipoprotein; IL-1β, interleukin 1β; IL-6, interleukin 6; TNF-α, tumour necrosis factor α; PLTP, phospholipid transfer protein; ATR-, angiotensin type 2 receptor; NO, nitric oxide and ET-1, endothelin 1.