Farnesoid X receptor (FXR)

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Upregulation of microRNA-23b-3p induced by farnesoid X receptor regulates the proliferation and apoptosis of osteosarcoma cells

Upregulation of microRNA-23b-3p induced by farnesoid X receptor regulates the proliferation and apoptosis of osteosarcoma cells

Fig. 1 Correlation of farnesoid X receptor (FXR) and microRNA-23b-3p expression in osteosarcoma (OS) cells and miR-23b-3p specifically targets cyclin G1 (CCNG1). As FXR might regulate the expression of miR-23b-3p in OS cells, we measured the expressions of FXR and miR-23b-3p in normal osteoblasts (hFOB1.19) and five osteosarcoma cell lines (MG-63, HOS, U2OS, SAOS2, SJSA1). a The relative expression levels of FXR were much downregulated in OS cell lines, especially in MG-63 cells. b The expressions of miR-23b-3p were obviously decreased, especially in MG-63 cells compared with hFOB1.19 cells. c Scatter plots showed the correlation of FXR and miR-23b-3p expression in normal osteoblasts and five osteosarcoma cell lines (Pearson ’ s coefficient test R 2 = 1.00, P = 0.0028). d The changes of miR-23b-3p levels were measured under different concentrations of the FXR agonist, GE4064 (0, 0.5, and 5 μ M). e TargetScan predicted that the fragment of CCNG1-3 ′ -UTR contained a binding site of miR-23b-3p. f The correlation between miR-23b-3p and CCNG1 was verified by luciferase reporter assay. Each value represents mean ± SEM ( n = 3). GAPDH and U6 served as internal controls for cellular genes and miR-23b-3p, respectively. ** p < 0.01 vs. hFOB1.19 cells or blank group;
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Inhibitory Effects of Bile Acids and Synthetic Farnesoid X Receptor Agonists on Rotavirus Replication

Inhibitory Effects of Bile Acids and Synthetic Farnesoid X Receptor Agonists on Rotavirus Replication

In the small intestines, where rotavirus replication occurs, de novo synthesis of lipids and absorption of dietary lipids affect cellular lipid contents in the epithelial cells (19). In the intes- tinal lumen, bile acids emulsify fats to form micelles to aid their absorption. Bile acids are synthesized from cholesterol in the liver, stored at the gallbladder, and released into the duode- num. The primary bile acids, cholic acid (CA) and chenode- oxycholic acid (CDCA), are synthesized in the liver from cho- lesterol by enzymes, including cholesterol 7 ␣ -hydroxylase, and subsequently conjugated with taurine or glycine to enhance affinity to both acids and bases. Primary bile acids are trans- formed by intestinal bacteria into secondary bile acids, deoxy- cholic acid (DCA), lithocholic acid (LCA), and ursodeoxy- cholic acid (UDCA) (11). While the secreted bile acids travel through the intestinal tracts, they are reabsorbed in the ileum and returned to the liver via the portal vein (25). This entero- hepatic circulation is essential in maintaining an effective con- centration of bile acids and cholesterol homeostasis. One of the bile acid receptors is farnesoid X receptor (FXR) (12, 27, 34). The activation of FXR by bile acids induces the expression of various proteins, including small heterodimer partner (SHP), which represses the expression of cholesterol 7 ␣ -hy- * Corresponding author. Mailing address: Department of Diagnos-
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Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra  and extrahepatic cholestasis

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra and extrahepatic cholestasis

Farnesoid X receptor (FXR) is a bile acid–activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of trans- porter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct–ligation and α-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expres- sion of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.
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Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis

Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis

Abstract: Non-alcoholic steatohepatitis (NASH), characterized by hepatocyte injury, inflammation, and fibrosis, is the main cause of chronic liver disease in the Western world. There are currently no approved pharmacological therapies for NASH, underscoring the urgent need for effective treatments. The farnesoid X receptor (FXR) has emerged as an attractive target for the treatment of metabolic and chronic liver diseases. EDP-305 is an FXR agonist currently in phase 2 clinical trials for Primary Biliary Cholangitis (PBC) and NASH. Here, we demonstrate that EDP-305 is a selective and potent FXR agonist that regulates multiple pathways relevant to NASH progression. EDP-305 exhibits anti-fibrotic and anti-inflammatory gene signatures in human macrophage and stellate cell lines, as well as favorable effects on lipid metabolism in hepatocytes, including enhanced low density lipoprotein (LDL)-cholesterol uptake and decreased triglyceride accumulation. The therapeutic potential of EDP-305 was further evaluated in two murine models of NASH: a streptozotocin-high fat diet STAM TM model and a dietary induced NASH (DIN) model driven by high fat, cholesterol, and fructose feeding. In both NASH models, EDP-305 significantly decreased hepatocyte ballooning and lowered the non-alcoholic fatty liver disease (NAFLD) activity score. EDP- 305 also significantly attenuated hepatic steatosis and dyslipidemia observed in the DIN mouse model. Conclusion: EDP-305 is a potent FXR agonist with a favorable gene expression profile for NASH treatment as evidenced by the hepato-protective and anti-steatotic effects observed in vivo. The preclinical characterization of EDP-305 presented here suggests that it holds promise for the treatment of NASH.
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Farnesoid X receptor is essential for normal glucose homeostasis

Farnesoid X receptor is essential for normal glucose homeostasis

The farnesoid X receptor (FXR; NR1H4) is a member of the nuclear receptor superfamily that is primarily expressed in liver, kidney, and intestine. It forms a heterodimer with retinoid X receptor and binds inverted repeats of 2 AGGTCA half sites separated by 1 nucleotide, insulin receptor 1 (IR-1), to regulate target gene transcription. Bile acids are its endogenous ligands (1–3), and FXR plays an essential role in the feedback regulation of bile acid biosynthesis through repression of the key enzyme cholesterol-7α hydroxylase (CYP7A1) (4). FXR activation induces expression of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which inhibits CYP7A1 gene expression by blocking the activity of another orphan receptor, the liver receptor homolog (LRH-1; NR5A2). Studies with SHP –/– mice confirmed the importance of this nuclear recep-
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Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis

Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in the world. The clinical-histological spectrum of NAFLD includes two major phenotypes, namely nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), the latter being associated with a relatively greater risk of cirrhosis and hepatocellular carcinoma. It is known that insulin resistance, lipotoxicity, oxidative stress and inflammatory factor represent important risk factors for the development of NASH, yet the exact mechanisms controlling the disease pathogenesis remain largely undefined and will require novel therapeutic approaches to prevent the transition from NAFLD to NASH. A promising new approach along these lines is based on recent discoveries of the key role played by bile acids (BAs) in regulating liver and metabolic homeostasis by activating various receptors, including farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). 1,2
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Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

influences NAFLD pathogenesis. Here, a murine model of high-fat diet–induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota–associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment.
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Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism

Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism

Recent evidence suggests that modulation of farnesoid X receptor (FXR) signaling has beneficial effects on the development of obesity (8–11). FXR is a bile acid-activated nuclear receptor that regulates the homeostasis of bile acids, lipids, and glucose (12–14). Endogenous ligands of FXR include bile acids such as cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) (14, 15). UDCA is used to treat human liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) (16). Further, UDCA was found to improve NASH, insulin resistance, and high-fat diet (HFD)-induced obesity through suppression of FXR signaling, which is manifested by a significant reduction of FXR and fibroblast growth factor 19 (FGF19) levels coupled with elevation of cholesterol 7 ␣ -hydroxylase (CYP7A1) expression in the intestine (17). Interestingly, tauro- ␤ -muricholic acid (T- ␤ -MCA) was also identified as a naturally occurring FXR antagonist that inhibits FXR signaling in vivo in mouse intestine (9, 18). Previous studies showed that tempol, an antioxidant, and antibiotic treatments resulted in reduction of the genus Lactobacillus, thus improving obesity, NAFLD, and insulin resistance via inhibition of intestinal FXR signaling (9, 11). However, T- ␤ -MCA is rapidly metabolized in the ileum by bacterial bile salt hydrolase (BSH) through deconjugation, yielding ␤ -MCA and taurine (19–21). Therefore, a new high-affinity intestinal FXR antagonist, glycine- ␤ -muricholic acid (Gly-MCA), was designed that is structurally and functionally similar to T- ␤ -MCA and that demonstrated stability in the gut by its resistance to hydrolysis by BSH. Gly-MCA improved HFD-induced obesity and insulin resistance (11); however, the underlying mechanisms by which Gly-MCA alters the gut microbiota population and its impact on host metabolism remain largely undeter- mined.
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Effective fecal microbiota transplantation for recurrent Clostridioides difficile infection in humans is associated with increased signalling in bile acid farnesoid X receptor fibroblast growth factor pathway

Effective fecal microbiota transplantation for recurrent Clostridioides difficile infection in humans is associated with increased signalling in bile acid farnesoid X receptor fibroblast growth factor pathway

The mechanisms of efficacy for fecal microbiota transplantation (FMT) in treating recurrent Clostridioides difficile infection (rCDI) remain poorly defined, with restored gut microbiota-bile acid interactions representing one possible explanation. Furthermore, the potential implications for host physiology of these FMT-related changes in gut bile acid metabolism are also not well explored. In this study, we investigated the impact of FMT for rCDI upon signalling through the farnesoid X receptor (FXR)-fibroblast growth factor (FGF) pathway. Herein, we identify that in addition to restoration of gut microbiota and bile acid profiles, FMT for rCDI is accompanied by a significant, sustained increase in circulating levels of FGF19 and reduction in FGF21. These FGF changes were associated with weight gain post-FMT, to a level not exceeding the pre-rCDI baseline. Collectively, these data support the hypothesis that the restoration of gut microbial communities by FMT for rCDI is associated with an upregulated FXR-FGF pathway, and highlight the potential systemic effect of FMT.
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Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma

Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma

The association between the temporal activation of Wnt/β-catenin pathway and the spontaneous hepatocellular carcinoma (HCC) development in Farnesoid X receptor (FXR) knockout mice is not well understood. We found that Huh7 cells depleted with FXR by RNAi showed enhanced cell growth, migration and invasion in vitro and accelerated tumor xenografts formation in nude mice. And these phenotypes were attenuated by simultaneous knockdown of β-catenin with RNAi. Furthermore, we identified that FXR could bind with β-Catenin through AF1 domain, and disrupt the assembly of the core β-Catenin/TCF4 complex. Activation of FXR attenuated the DNA-binding activity of β-Catenin/TCF4, and subsequently, its targeting gene-cyclin D1 expression. Importantly, FXR expression was markedly reduced in human HCC, an event which correlated with aberrant activation of β-Catenin. These data identified FXR as a negative regulator of HCC development through direct suppression of Wnt/β-catenin pathway.
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Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo

Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo

pathway, with both basolateral Na + /K + ATPase activity, and apical CFTR Cl − channel currents being attenuated upon treat- ment. Thus, activation of the FXR prevents fl uid secretion by inhibiting both the driving force for Cl − uptake across the baso- lateral membrane, and its exit across the apical membrane via CFTR. Furthermore, the effects of FXR activation on inhibition of transport protein function appear to be speci fi c, since basolat- eral K + channel currents, which are necessary to drive Cl − secre- tion, were found to be unaltered by GW4064 (data not shown). Thus, the effects of GW4064 do not appear to be due to a loss of cell viability, and this is further supported by observations that, even at the highest concentrations tested, GW4064 did not alter TER or LDH release from cultured cells, nor did it have any apparent toxicity in vivo. Furthermore, at concentrations similar to those used in the current study, previous studies have shown that GW4064 is devoid of liver and kidney toxicity. 32 33
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Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

The nuclear receptor FXR is classically associated with bile acid homeostasis in the body and its target genes impact on the metabolic and transporter-mediated clearance of both bile acids and their precursors [15]. However, FXR activation has also been reported to elicit a number of other phenotypes, including cell death. To confirm this phenotype in breast cancer cell lines, we examined the effect of the endogenous ligand CDCA and the more potent and selective artificial ligand GW4064 [31]. Four cell lines were chosen to represent different breast cancer phenotypes: normal (i.e. MCF-10A), receptor positive tumour (i.e. MCF-7) and triple negative tumours (i.e. MDA-MB-231 and MDA-MB-468). We confirmed that FXR is expressed in these cell lines, and for MCF-7 and MDA-MB-231 cells that the FXR- dependent signalling cascade is intact, with activation of SHP expression in response to FXR activation (supplemental figure S1).
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TO901317 regulating apolipoprotein M expression mediates via the farnesoid X receptor pathway in Caco-2 cells

TO901317 regulating apolipoprotein M expression mediates via the farnesoid X receptor pathway in Caco-2 cells

TO901317 caused an increased mRNA level of Short Het- erodimer Partner (SHP) in HepG2 cells. In contrast, the SHP mRNA level was not affected by the oxysterols. Enhanced expression of SHP could inhibit LRH-1- mediated trans-activation of apoM promoter in HepG2 cells [11]. SHP is an inhibitory nuclear receptor activated by the FXRs that interacts physically with many nuclear receptors including LRH-1. Furthermore, it has been reported that TO901317 is a dual LXR/FXR agonist that activates FXR more efficiently than its natural ligand, the bile acids [21]. Based on the findings described above, the TO901317 downregulating apoM expression in hepatic cells may be due to the activation of the FXR/SHP path- way that inhibits LRH-1.
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Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets

Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets

incubation with GW4064 (1,10 M) or vehicle (containing DMSO (0.1% (v/v)) for 5 min. Blood was perfused for 10 min, after which thrombus development was assessed by measurement of fluorescence intensity. In comparison with control samples (Fig 5 A), 10 M GW4064 inhibited the thrombus fluorescence intensity by 65% (Fig 5 C-D). These data suggest that GW4064 is able to modulate thrombus formation under arterial flow conditions in whole blood. To determine whether the effects of GW4064 on thrombus formation in vitro were due to inhibition of initial entrapment of platelets on collagen, or due to the inhibition of platelet aggregation and therefore thrombus growth, perfusion of blood was also performed in the presence and absence of the IIb3 antagonist integrilin (4µM). In the presence of integrilin, GW4064 (10 μM) did not affect platelet adhesion to collagen suggesting that the FXR agonist does not modulate GPIb-dependent adhesion under flow (Supplemental Fig 3). These data indicate that the inhibition of thrombus formation by GW4064 is likely due to its ability reduce platelet activation following adhesion.
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Farnesoid X receptor represses hepatic human APOA gene expression

Farnesoid X receptor represses hepatic human APOA gene expression

repressor, it has no DNA binding motif (56) but interacts with sev- eral nuclear receptors, such as LRH-1 or HNF4α, thereby interfering with gene transcription. Recently, the SHP/LRH-1/CYP7A1 signal- ing pathway was disproved, and LRH-1 was identified as a master regulator of Cyp8b1 (57, 58). Since SHP is able to interact in vitro with multiple partners, the identification of the actual SHP targets is still an open quest. Our transgenic APOA mice fed with CA or pri- mary hepatocytes incubated with FXR activators were found to have more Shp and less APOA gene expression. We therefore wondered whether Shp induction could repress APOA. However, dose response transfection experiments with SHP expression plasmid showed that SHP did not repress and instead increased the APOA promoter activity in HepG2 as well as in COS-7 cells (Supplemental Figure 6). Conversely, FXR directly repressed APOA promoter activity by binding to a DR-1 also recognized by HNF4α. This was verified by ChIP assay, which impressively confirmed that the DR-1 element at the –826- to –814-bp region of the APOA promoter is occupied by HNF4α, whereas CA activation leads to a switch of occupancy of the site by FXR (Figure 7E). Taken together, our data suggest that SHP does not regulate the APOA promoter in contrast to FXR.
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Treatment of mouse liver slices with cholestatic hepatotoxicants results in down-regulation of Fxr and its target genes

Treatment of mouse liver slices with cholestatic hepatotoxicants results in down-regulation of Fxr and its target genes

The nuclear receptor farnesoid X receptor (FXR/NR1H4, in the remaining part of the manuscript FXR symbol will be used) is considered as a master regulator of BA homeostasis. FXR upon BA binding regulates expression of several genes involved in BA homeostasis in the liver [2]. Impairment of FXR signaling and its downstream target genes can result in intrahepatic cholestasis. For example, dysregulation or mutations in genes encoding for bile salt export pump (BSEP), multidrug resistance protein 3 (MDR3) [6], or cholesterol 7a-hydroxylase (CYP7A1) [7] and bile acid-CoA:amino acid N-acyltransferease (BAAT) can evoke cholestasis [8]. Other nuclear receptors (NRs), such as pregnane X receptor (PXR), vitamin D (1,25- dihydroxyvitamin D3) receptor (VDR), and constitutive androstane receptor (CAR) are known to be involved in BA detoxification by regulating expression of genes involved in phase I and II reactions [9]. Moreover, FXR also plays a major role in regulation of lipid and glucose metabolism [2]. Therefore, FXR antagonism does not only induce cholestasis but also leads to increased accumulation of hepatic triglycerides [2]. For that reason, activation of FXR is used in the treatment of cholestasis and non- alcoholic steatohepatitis (NASH) [9].
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The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

Bile acids are steroid molecules generated in the liver by cholesterol metabolism [4]. In addition to their role in nutrients absorption bile acids function as signaling hormones by activating a family of receptors that includes nuclear receptors such as the Farnesoid-x-receptor (FXR) [6], Constitutive Androstane Receptor (CAR), [7], Pregnane-x-receptor (PXR) [8], liver-x-receptor (LXR) [9] and the Vitamin D receptor (VDR), and G-protein coupled receptors (i.e. TGR5 or GPBAR1) [10, 11]. Bile acids activate these receptors with a different rank of potency [12, 13], with primary bile acids functioning as preferential ligands for FXR and secondary bile acids for GPBAR1. GPBAR1 is a member of the rhodopsin- like superfamily of G-protein-coupled receptor. GPBAR1 is highly represented in the gastrointestinal tract and non-parenchymal liver cells oversighting on a variety of homeostatic and regulatory functions [9–12]. Once activated by secondary bile acids (i.e. litocholic acid (LCA) and deoxycholic acid (DCA) and their tauro- and glyco-conjugated forms) GPBAR1 modulates multiple targets by genomic and non-genomic effects [9, 10]. GPBAR1 is expressed in epithelial, endocrine [11] and neuronal cells, in the stomach and intestine, and mice harboring a disrupted GPBAR1 are more prone to develop a severe intestinal inflammation [14].
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<p>Evaluating the Therapeutic Potential of Cenicriviroc in the Treatment of Nonalcoholic Steatohepatitis with Fibrosis: A Brief Report on Emerging Data</p>

<p>Evaluating the Therapeutic Potential of Cenicriviroc in the Treatment of Nonalcoholic Steatohepatitis with Fibrosis: A Brief Report on Emerging Data</p>

Although early clinical data support direct antifibrotic effects of CVC, effects on metabolic components of NAFLD and NASH have been limited. Combination approaches to incorporate novel investigational agents tar- geting both metabolic and fibrosis endpoints are under active exploration to augment efficacy in histologic and clinical endpoints. In this context, the phase 2b TANDEM trial 33 is a randomized, placebo-controlled, multicenter trial evaluating the combination of CVC and tropifexor (TXR). TXR is a non-bile acid farnesoid X receptor (FXR) agonist which has demonstrated important effects on bile acid, glucose, and lipid metabolism. 34,35 TXR alone has shown efficacy in preclinical models of NASH in which it has reduced bile acid and triglyceride synthesis, and has decreased hepatic steatosis, hepatic inflammation, and hepatocyte ballooning. 36 Preclinical and phase 1 studies evaluating the combination of TXR plus CVC have revealed a significant reduction in hepatic inflammation and ballooning with acceptable safety and tolerability. The all-oral combination of TXR and CVC is anticipated to demonstrate antisteatotic, anti-inflammatory and antifibro- tic effects. The primary objective of the phase 2b TANDEM trial is to evaluate the safety and tolerability of a TXR plus CVC combination regimen compared with TXR and CVC monotherapy in 200 patients with NASH and liver fibrosis stage F2/F3 over 48 weeks. The secondary objective will
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Current therapies in alleviating liver disorders and cancers with a special focus on the potential of vitamin D

Current therapies in alleviating liver disorders and cancers with a special focus on the potential of vitamin D

The farnesoid X receptor belongs to the nuclear recep- tor family and is expressed in organs like the kidney, liver, adipose tissue and intestine. It influences the synthesis of bile acids, cholic and chenodeoxycholic acids which is through two known pathways. The classical or neu- tral pathway instigated by 7α- hydroxylation produces both bile acids, whereas the acidic pathway commen- cing with the side chain hydroxylation (C27) produces only chenodeoxycholic acid. A major difference is that the key enzyme cytochrome P450 oxidase and the sterol 27-hydroxylase CYP27A1 of the acidic pathway are neither regulated by the bile acids nor its levels altered in FXR-deficient mice. But FXR is involved in the down-regulation of expression of the microsomal rate-limiting enzyme CYP7A1 of the neutral pathway promoting it as a potential therapeutic agent [46]. Hypovitaminosis D is associated with increased body fat mass, and greater severity of NAFLD [47]. Hypo vitaminosis in NAFLD patients ’ needs to be demon- strated in future long term follow up studies to attri- bute a causal role to the vitamin, so that a therapeutic solution could be adopted.
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Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease

Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease

The farnesoid X receptor (FXR; gene symbol NR1H4) is a nuclear receptor that functions as the main sensor of intracellular bile acid levels [7-9]. The human NR1H4 gene is located on chromosome 12 and is composed of 11 exons and 10 introns [10]. The translation initiation codon of the NR1H4 gene lies at the 3 0 end of exon 3, whereas exons 1 and 2, together with the 5 0 region of exon 3, contain the 5 0 untranslated region (5’-UTR). Multiple FXR isoforms can be generated via alternative promoter usage and alternative splicing, and these iso- forms may have differential transactivation abilities on specific target promoters [11]. FXR typically acts by binding to FXR response elements within the target pro- moters as heterodimers with another member of the nu- clear receptor family, retinoid X receptor-α (RXRα) [12]. In response to elevated levels of intracellular bile acids, activated FXR is well known to induce protective gene expression circuits against bile acid toxicity in the liver and intestine [13]. Expression of bile acid efflux systems in ileocytes (organic solute transporter α/β; OSTα/β) [14,15] and hepatocytes (bile salt export pump; BSEP) [16-18] is upregulated by bile acid-activated FXR, while the expression of the respective bile acid uptake systems apical sodium-dependent bile acid transporter (ASBT) [19] and Na + -taurocholate cotransporting polypeptide (NTCP) [20,21] is suppressed by it. FXR also represses transcription of three genes coding for bile acid synthe- sizing enzymes, namely cholesterol-7α-hydroxylase (CYP7A1), sterol-12α-hydroxylase (CYB8B1), and sterol- 27-hydroxylase (CYP27A1) [22,23]. Thus, elevated levels of bile acids can suppress their own de novo production through a negative feedback loop involving FXR. In addition, FXR regulates several genes that can protect against intestinal inflammation and bacterial overgrowth [24-26]. Fxr-deficient mice have increased ileal concen- trations of gut bacteria and exhibit defects in the integ- rity of the intestinal epithelial barrier. In agreement with this, the products of a number of genes that are regu- lated by Fxr in the ileum, including angiogenin (Ang1), inducible nitric oxide synthase (iNos), and interleukin-18 (Il-18), are known to have antimicrobial actions [26]. Furthermore, it has been reported that reduced expres- sion of Fxr/FXR is associated with colon inflammation in rodent models of colitis and in CD patients [25]. Re- cently, FXR activation was shown to decrease NF-κB- mediated immune responses and intestinal permeability in mouse models of colitis [27]. It was subsequently shown that intestinal inflammation reduces FXR activa- tion as well as the expression of FXR target genes such as intestinal bile acid-binding protein (IBABP) and fibro- blast growth factor 15/19 (FGF15/19) [28]. In agreement with this, it has been proposed that FXR may contribute
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