Farnesoid X Receptor Activation Enhances Transforming Growth Factor β-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells
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Abstract:
Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)—but not an antagonist (guggulsterone)—induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor β (TGF-β). FXR agonist treatment enhanced TGF-β-induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-β. Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates.Keywords:
Farnesoid X receptor
Chenodeoxycholic acid
Obeticholic acid
Farnesoid X receptor
Enterohepatic circulation
Pregnane X receptor
Chenodeoxycholic acid
FGF19
Deoxycholic acid
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Studies show that dysregulation of bile acids could affect insulin sensitivity and glucose metabolism.Bile acids are metabolic regulators that act as signaling molecules through receptor-dependent and -independent pathways.The most prominent signaling molecules mediating bile acid signaling are the nuclear receptor farnesoid X receptor(FXR) and the membrane receptor G protein-coupled bile acid receptor 5 (TGR5).Dysregulation of these pathways might contribute to the reduction of insulin sensitivity.Therefore,the manipulation of bile acid homeostasis,especially the regulation of its signaling pathways might be a potential treatment of type 2 diabetes.
Key words:
Bile acids; Type 2 diabetes mellitus; Farnesoid X receptor; G protein-coupled bile acid receptor 5
Farnesoid X receptor
Liver receptor homolog-1
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The relationship between BA (bile acid) secretion (measured by GC–MS) and the expression of genes (measured by reverse transcription real-time PCR) involved in liver BA transport and metabolism was investigated at 20 and 32 weeks during rat hepatocarcinogenesis. A progressive loss of mRNA for transporters (more marked for Ntcp, Bsep and Mrp2 than for Oatp1/Oatp1a1, Oatp2/Oatp1a4 and Oatp4/Oatp1b2) was found. The mRNA levels of Cyp7a1 and the nuclear receptors FXR (farnesoid X receptor), SHP (small heterodimer partner) and FTF (α-fetoprotein transcription factor) were not modified, whereas those of Cyp8b1 were enhanced and those of Cyp27 were reduced. Biliary secretion of CA (cholic acid) remained unchanged, whereas that of CDCA (chenodeoxycholic acid) and other non-C12-hydroxylated BAs was diminished. The re-appearance of ‘flat-BAs’ (mainly allo-BAs at 20 weeks and Δ4-unsaturated-BAs at 32 weeks) probably reflects the progressive decrease observed in the expression of 3-oxo-Δ4-steroid 5β-reductase, together with the maintenance of steroid 5α-reductase type I. A significant correlation between the 5α-reductase/5β-reductase ratio and bile output of ‘flat-BAs’ was found. In conclusion, during rat hepatocarcinogenesis, the expression of transporters/enzymes responsible for BA homoeostasis is changed due to mechanisms other than those controlled by FXR/SHP/FTF. These modifications result in the re-appearance of ‘flat-BAs’, together with an increased CA/CDCA ratio in bile.
Farnesoid X receptor
Chenodeoxycholic acid
Small heterodimer partner
CYP8B1
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Farnesoid X receptor
CYP8B1
Enterohepatic circulation
Small heterodimer partner
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In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.
Farnesoid X receptor
Energy homeostasis
Homeostasis
Carbohydrate Metabolism
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This article discusses the impact of bile acid sequestrants (BAS) on cardiovascular risk factors (CVRFs), on the basis of recent (pre)clinical studies assessing the metabolic impact of modulation of enterohepatic bile acid signaling via the bile acid receptors farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5).BAS decrease low-density lipoprotein-cholesterol by stimulating de novo hepatic bile acid synthesis and lowering intestinal lipid absorption, and improve glucose homeostasis in type 2 diabetes mellitus, at least in part by increasing GLP-1 production, via intestinal TGR5- and FXR-dependent mechanisms. Intestinal and peripheral FXR and TGR5 modulation also affects peripheral tissues, which can contribute to the reduction of CVRFs.Bile acids are regulators of metabolism acting in an integrated interorgan manner via FXR and TGR5. Modulation of the bile acid pool size and composition, and selective interference with their receptors could, therefore, be a therapeutic approach to decrease CVRFs. Even though clinical cardiovascular outcome studies using BAS are still lacking, the existing data point to BAS as an efficacious pharmacological approach to reduce CVRFs.
Farnesoid X receptor
Enterohepatic circulation
CYP27A1
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The gut microbiota plays a crucial role in regulating many physiological systems of the host, including the metabolic and immune system. Disturbances in microbiota composition are increasingly correlated with disease; however, the underlying mechanisms are not well understood. Recent evidence suggests that changes in microbiota composition directly affect the metabolism of bile salts. Next to their role in digestion of dietary fats, bile salts function as signaling molecules for bile salt receptors such as Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor (TGR5). Complementary to their role in metabolism, FXR and TGR5 are shown to play a role in intestinal homeostasis and immune regulation. This review presents an overview of evidence showing that changes in bile salt pool and composition due to changes in gut microbial composition contribute to the pathogenesis of inflammatory bowel disease and metabolic disease, possibly through altered activation of TGR5 and FXR. We further discuss how dietary interventions, such as pro- and synbiotics, may be used to treat metabolic disease and inflammatory bowel disease (IBD) through normalization of bile acid dysregulation directly or indirectly through normalization of the intestinal microbiota.
Farnesoid X receptor
Synbiotics
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Bile acids play a critical role in the regulation of glucose, lipid, and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, aka TGR5). Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). Bile acids have both pro- and anti-inflammatory actions through FXR and TGR5 in the intestine and liver. In the intestine, bile acids activate FXR and TGR5 to stimulate stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion. FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases, such as diabetes and NAFLD.
Farnesoid X receptor
Liver disease
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Recent studies show that bile acids are involved in glucose and energy homeostasis through activation of G protein coupled membrane receptor (TGR5) and farnesoid X receptor (FXR). A few researches have explored changes of TGR5 and FXR in animals with impaired glucose regulation. This study aimed to observe changes of plasma total bile acids (TBA), glucagon-like-peptide 1 (GLP-1), fibroblast growth factor 15 (FGF15), intestinal expressions of TGR5 and FXR, and correlations between them in rats with glucose intolerance. Besides plasma fasting glucose, lipid, TBAs, alanine transaminase (ALT), active GLP-1(GLP-1A) and FGF15, a postprandial meal test was used to compare responses in glucose, insulin and GLP-1A among groups. The expressions of TGR5 and FXR in distal ileum and ascending colon were quantified by real-time PCR and western blot. TGR5 expression was significantly decreased in distal ileum in DM group compared to other groups, and TGR5 and FXR expressions in ascending colon were also decreased in DM group compared to other groups. Correlation analysis showed correlations between TBA and GLP-1A or FGF15. GLP-1A was correlated with TGR5 mRNA expression in colon, and FGF15 was correlated with FXR mRNA expression in colon. These results indicates that bile acid-TGR5/FXR axis contributes to glucose homeostasis.
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Farnesoid X receptor
Metabolic pathway
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Citations (228)