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

Abstract

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 metabolism but also in the integration of sterol, fatty acid and glucose metabolism.

Figure 1. Mechanism of action of LXR and FXR

a | The basic structure of a nuclear receptor, highlighting the DNA-binding and ligand-binding domains. b | Liver X receptor (LXR) forms an obligate heterodimer with retinoid X receptor (RXR) that binds to a DR4 (direct repeat spaced by four nucleotides) LXRE (LXR response element) in the regulatory regions of target genes, thereby repressing gene expression. Following ligand binding to LXR or RXR, the heterodimer changes conformation, which leads to the release of co-repressors and the recruitment of co-activators. This results in the transcription of target genes. Similarly, farnesoid X receptor (FXR) forms a heterodimer with RXR and binds to the FXR response element (FXRE), which is typically an inverse repeat spaced by one nucleotide (IR1), in its target genes to induce gene expression. AF domain, activation function domain; C-terminal, carboxy-terminal; N-terminal, amino-terminal.

Figure 2. Coordinated effects of LXR on metabolism

Liver X receptor (LXR) mediates effects on multiple metabolic pathways in a tissue-specific manner. In peripheral cells such as macrophages, LXR induces expression of IDOL (inducible degrader of the low-density lipoprotein receptor (LDLR)), which promotes the proteasome-mediated degradation of LDLR and thus results in reduced LDL uptake into the cell. In peripheral cells, LXR also increases ARL7 (ADP-ribosylation factor-like 7), ABCA1 (ATP-binding cassette transporter A1) and ABCG1 expression, promoting the movement of cholesterol to the plasma membrane and cholesterol efflux and transfer to lipid-poor molecules such as apolipoprotein AI (APOAI) and pre-β high-density lipoprotein (HDL), thus increasing plasma HDL levels. APOE promotes the return of HDL to the liver. Furthermore, in the liver, LXR promotes cholesterol conversion to bile acids by cytochrome P450 7A1 (CYP7A1). It also promotes fatty acid synthesis via induction of sterol-regulatory element-binding protein 1C (SREBP1C) and its targets, fatty acid synthase (FAS), acetyl CoA carboxylase (ACC) and steroyl CoA desaturase 1 (SCD1). Secretion of triglyceride-rich very low-density lipoproteins (VLDLs) by the liver transports lipids to peripheral tissues, including adipose tissue, where the action of lipoprotein lipase (LPL) liberates fatty acids from VLDL. In adipose tissue, LXR regulates the expression of lipid-binding and metabolic proteins such as APOD and SPOT14 and may promote the breakdown of fatty acids through their β-oxidation (which occurs in mitochondria). LXR also promotes glucose uptake via induction of glucose transporter type 4 (GLUT4). Finally, in the intestine, LXR inhibits cholesterol absorption by inducing the expression of the ABC transporters ABCG5 and ABCG8 and possibly ABCA1.

Figure 3. Coordinated effects of FXR on metabolism

Farnesoid X receptor (FXR) mediates effects on multiple metabolic pathways in a tissue-specific manner. In the liver, FXR reduces conversion of cholesterol to bile acids by downregulating the expression of enzymes involved in bile acid synthesis, such as cytochrome P450 7A1 (CYP7A1) and CYP8B1. FXR also reduces bile acid toxicity in the liver by increasing other bile acid-modifying enzymes including sulphotransferase 2A1 (SULT2A1), UDP-glucuronosyltransferase 2B4 (UGT2B4) and CYP3A4. Bile acids are conjugated to either glycine or taurine before secretion into the bile; FXR enhances bile acid conjugation by increasing the expression of bile acid CoA synthase (BACS) and bile acid CoA–amino acid N-acetyltransferase (BAAT), and FXR promotes the transport of bile acids to the gall bladder via bile salt export pump (BSEP), multidrug resistance protein 2 (MDR2) and MDR3 (membrane transport proteins are depicted as ovals). Within the intestine, FXR reduces bile acid absorption via downregulation of the apical sodium-dependent bile acid transporter (ASBT), promotes bile acid movement across the enterocyte via ileal bile acid binding-protein (IBABP) and promotes recycling of bile acids to the liver via organic solute transporter-α (OSTα) and OSTβ. In addition, FXR reduces hepatic uptake of bile acids by reducing the expression of organic anion transporting polypeptide (OATP) and sodium taurocholate cotransporting polypeptide (NTCP). FXR also promotes the release of fibroblast growth factor 15 (FGF15) in mice or FGF19 in humans from the intestine. FGF15 or FGF19 travel to the liver, acting on FGF4 receptor (FGF4R) to reduce CYP7A1 expression and thus repress bile acid synthesis. In the liver, FXR also acts on glucose metabolism by reducing gluconeogenesis via the downregulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key enzymes in the glucose synthesis pathway. Futhermore, FXR reduces lipogenesis via inhibition of sterol-regulatory element-binding protein 1C (SREBP1C) and fatty acid synthase (FAS).