Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

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Bile acid diarrhoea: pathophysiology, diagnosis and management

Frontline Gastroenterology ◽

10.1136/flgastro-2020-101436 ◽

2020 ◽

pp. flgastro-2020-101436

Author(s):

Alexia Farrugia ◽

Ramesh Arasaradnam

Keyword(s):

Bile Acid ◽

Enterohepatic Circulation ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Feedback Loops ◽

Farnesoid X Receptor ◽

Delay In Diagnosis ◽

Negative Feedback Loops ◽

Irritable Bowel ◽

Fibroblast Growth Factor 19

The actual incidence of bile acid diarrhoea (BAD) is unknown, however, there is increasing evidence that it is misdiagnosed in up to 30% with diarrhoea-predominant patients with irritable bowel syndrome. Besides this, it may also occur following cholecystectomy, infectious diarrhoea and pelvic chemoradiotherapy.BAD may result from either hepatic overproduction of bile acids or their malabsorption in the terminal ileum. It can result in symptoms such as bowel frequency, urgency, nocturnal defecation, excessive flatulence, abdominal pain and incontinence of stool. Bile acid synthesis is regulated by negative feedback loops related to the enterohepatic circulation, which are dependent on the farnesoid X receptor and fibroblast growth factor 19. Interruption of these feedback loops is thought to cause bile acid overproduction leading to BAD. This process may occur idiopathically or following a specific trigger such as cholecystectomy. There may also be an interplay with the gut microbiota, which has been reported to be significantly different in patients with severe BAD.Patients with suspected BAD are investigated in various ways including radionucleotide imaging such as SeHCAT scans (though this is not available worldwide) and blood tests. However, other methods such as bile acid measurement in stool (either spot test or 48 hours samples) and urine tests have been explored. Importantly, delay in diagnosis and treatment of BAD greatly affects patient’s quality of life and may double the overall cost of diagnosis.

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Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice

Hepatology ◽

10.1002/hep.25740 ◽

2012 ◽

Vol 56 (3) ◽

pp. 1034-1043 ◽

Cited By ~ 204

Author(s):

Bo Kong ◽

Li Wang ◽

John Y.L. Chiang ◽

Youcai Zhang ◽

Curtis D. Klaassen ◽

...

Keyword(s):

Bile Acid ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Farnesoid X Receptor ◽

Tissue Specific ◽

Expression Of Genes

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Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00223.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. G554-G573 ◽

Cited By ~ 13

Author(s):

John Y. L. Chiang ◽

Jessica M. Ferrell

Keyword(s):

Bile Acid ◽

Fatty Liver ◽

Bile Acids ◽

G Protein ◽

Liver Diseases ◽

Metabolic Diseases ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Bile Acid Receptors ◽

G Protein Coupled

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.

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Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90371.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. G1119-G1129 ◽

Cited By ~ 21

Author(s):

Pilar Martínez-Fernández ◽

Loreto Hierro ◽

Paloma Jara ◽

Luis Alvarez

Keyword(s):

Bile Acid ◽

Hepg2 Cells ◽

Target Genes ◽

Constitutive Androstane Receptor ◽

Pregnane X Receptor ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Bile Secretion ◽

Farnesoid X Receptor ◽

Mrna Levels

Farnesoid X receptor (FXR) is a bile acid-sensing nuclear receptor that controls bile acid homeostasis. It has been suggested that downregulation of FXR contributes to the pathogenesis of an inherited disorder of bile secretion caused by mutations in ATP8B1. We have investigated the relationship between ATP8B1 knockdown and FXR downregulation in the human hepatoblastoma cell line HepG2. Transfection of HepG2 cells with ATP8B1 small interfering RNA (siRNA) duplexes led to a 60% reduction in the endogenous levels of ATP8B1 mRNA and protein and a concomitant decrease in FXR mRNA and protein content, as well as in FXR phosphorylation. This decrease was accompanied by a marked reduction in mRNA levels of a subset of FXR targets, such as bile salt export pump ( ABCB11), small heterodimer partner, and uridine 5′-diphosphate-glucuronosyltransferase. ATP8B1 inhibition specifically targeted FXR since mRNA expression of other prominent nuclear receptors, such as pregnane X receptor and constitutive androstane receptor, or liver-enriched transcription factors, such as hepatocyte nuclear factor 1α ( HNF-1α) and HNF-4α, was not altered. The expression of other key genes involved in bile acid synthesis, detoxification, and transport also remained unchanged upon ATP8B1 knockdown. Supporting the specificity of the effect, siRNA-mediated silencing of ABCB11, whose defect is associated with another inherited disorder of bile secretion, did not affect FXR expression. Treatment with the synthetic FXR agonist GW4064 was able to partially neutralize ATP8B1 siRNA-mediated FXR downregulation and fully counteract inhibition of FXR target genes. Collectively these findings indicate that ATP8B1 knockdown specifically downregulates FXR, and this action can be circumvented by treatment with FXR agonists.

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Tu1262 Obeticholic Acid, a Farnesoid X Receptor Agonist, Reduces Bile Acid Synthesis in Patients With Primary Bile Acid Diarrhea

Gastroenterology ◽

10.1016/s0016-5085(14)62881-x ◽

2014 ◽

Vol 146 (5) ◽

pp. S-797 ◽

Cited By ~ 1

Author(s):

Claire Vassie ◽

Jonathan D. Nolan ◽

Ian M. Johnston ◽

David Shapiro ◽

Julian R. Walters

Keyword(s):

Bile Acid ◽

Receptor Agonist ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Farnesoid X Receptor ◽

Obeticholic Acid ◽

Primary Bile Acid

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β-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90343.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. G996-G1003 ◽

Cited By ~ 56

Author(s):

Jyoti Sinha ◽

Frank Chen ◽

Tamir Miloh ◽

Robert C. Burns ◽

Zhisheng Yu ◽

...

Keyword(s):

Bile Acid ◽

Culture Media ◽

Retinoic Acid Receptor ◽

Cancer Cell Line ◽

Acid Synthesis ◽

Colon Cancer Cell Line ◽

Bile Acid Synthesis ◽

Dominant Negative ◽

Farnesoid X Receptor ◽

Site Directed Mutagenesis

β-Klotho, a newly described membrane protein, regulates bile acid synthesis. Fibroblast growth factor-15 (FGF-15) and FGF receptor-4 (FGFR4) knockout mice share a similar phenotype with β-Klotho-deficient mice. FGF-15 secretion by the intestine regulates hepatic bile acid biosynthesis. The effects of β-Klotho and FGF-15 on the ileal apical sodium bile transporter (ASBT) are unknown. β-Klotho siRNA treatment of the mouse colon cancer cell line, CT-26, and the human intrahepatic biliary epithelial cells (HIBEC) resulted in upregulation of endogenous ASBT expression that was associated with reduced expression of the farnesoid X receptor (FXR) and the short heterodimer partner (SHP). Silencing β-Klotho activated the ASBT promoter in CT-26, Mz-ChA-1 (human cholangiocarcinoma), and HIBEC cells. Site-directed mutagenesis of liver receptor homolog-1 (mouse) or retinoic acid receptor/retinoid X receptor (RAR/RXR) (human) cis-elements attenuated the basal activity of the ASBT promoter and abrogated its response to β-Klotho silencing. siSHP, siFXR, or dominant-negative FXR treatment also eliminated the β-Klotho response. FGF-15 secretion into cell culture media by CT-26 cells was diminished after siFGF-15 or siβ-Klotho treatment and enhanced by chenodeoxycholic acid. Exogenous FGF-19 repressed ASBT protein expression in mouse ileum, gallbladder, and in HIBEC and repressed ASBT promoter activity in Caco-2, HIBEC, and Mz-ChA-1 cells. Promoter repression was dependent on the expression of FGFR4. These results indicate that both β-Klotho and FGF-15/19 repress ASBT in enterocytes and cholangiocytes. These novel signaling pathways need to be considered in analyzing bile acid homeostasis.

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Dynamics of the enterohepatic circulation of bile acids in healthy humans

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00476.2020 ◽

2021 ◽

Author(s):

Frans Stellaard ◽

Dieter Lütjohann

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Enterohepatic Circulation ◽

Feedback Inhibition ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Healthy Humans

Regulation of bile acid metabolism is normally discussed as the regulation of bile acid synthesis, which serves to compensate for intestinal loss in order to maintain a constant pool size. After a meal, bile acids start cycling in the enterohepatic circulation. Farnesoid X receptor-dependent ileal and hepatic processes lead to negative feedback inhibition of bile acid synthesis. When the intestinal bile acid flux decreases, the inhibition of synthesis is released. The degree of inhibition of synthesis and the mechanism and degree of activation are still unknown. Moreover, in humans, a biphasic diurnal expression pattern of bile acid synthesis has been documented, indicating maximal synthesis around 3 pm and 9 pm. Quantitative data on the hourly synthesis schedule as compensation for intestinal loss are lacking. In this review, we describe the classical view on bile acid metabolism and present alternative concepts that are based on the overlooked feature that bile acids transit through the enterohepatic circulation very rapidly. A daily profile of the cycling and total bile acid pool sizes and potential controlled and uncontrolled mechanisms for synthesis are predicted. It remains to be elucidated by which mechanism clock genes interact with the Farnesoid X receptor-controlled regulation of bile acid synthesis. This mechanism could become an attractive target to enhance bile acid synthesis at night, when cholesterol synthesis is high, thus lowering serum LDL-cholesterol.

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ENDOCRINOLOGY IN PREGNANCY: Metabolic impact of bile acids in gestation

Acta Endocrinologica ◽

10.1530/eje-20-1101 ◽

2021 ◽

Vol 184 (3) ◽

pp. R69-R83

Author(s):

Hei Man Fan ◽

Alice L Mitchell ◽

Catherine Williamson

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Maternal Serum ◽

Farnesoid X Receptor ◽

Acid Uptake ◽

Glucose And Lipid Metabolism ◽

Bile Acid Uptake ◽

In Pregnancy

Bile acids are lipid-solubilising molecules that also regulate metabolic processes. Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are two bile acid receptors with key metabolic roles. FXR regulates bile acid synthesis in the liver and influences bile acid uptake in the intestine. TGR5 is mainly involved in regulation of signalling pathways in response to bile acid uptake in the gut and therefore prandial response. Both FXR and TGR5 have potential as therapeutic targets for disorders of glucose and/or lipid homeostasis. Gestation is also known to cause small increases in bile acid concentrations, but physiological hypercholanaemia of pregnancy is usually not sufficient to cause any clinically relevant effects. This review focuses on how gestation alters bile acid homeostasis, which can become pathological if the elevation of maternal serum bile acids is more marked than physiological hypercholanaemia, and on the influence of FXR and TGR5 function in pregnancy on glucose and lipid metabolism. This will be discussed with reference to two gestational disorders: intrahepatic cholestasis of pregnancy (ICP), a disease where bile acids are pathologically elevated, and gestational diabetes mellitus (GDM), characterised by hyperglycaemia during pregnancy.

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Abstract 5521: Activation of Farnesoid X Receptor (FXR) Reduces Atherosclerosis in LDLRKO and apoEKO Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_566-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Helen B Hartman ◽

Douglas C Harnish ◽

Mark J Evans

Keyword(s):

Bile Acid ◽

Ldl Cholesterol ◽

Atherosclerotic Lesion ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Western Diet ◽

Cholesterol Homeostasis ◽

Farnesoid X Receptor ◽

Protective Mechanism ◽

Lesion Development

The nuclear hormone receptors farnesoid X Receptor (FXR) and small heterodimer partner (SHP) regulate bile acid synthesis and cholesterol homeostasis in a complex fashion. In regard to atherosclerosis, FXR repression of bile acid synthesis has been proposed to be either detrimental due to reduced elimination of cholesterol or beneficial due to decreased cholesterol absorption. FXRKO mice have failed to resolved this question, with atherosclerotic lesions in FXRKO mice either enhanced (apoE, FXRdKO mice) or reduced (LDLR, FXRdKO mice). Here we demonstrate that the synthetic ligand FXR-450 blocked Western diet-mediated increases in VLDL and LDL cholesterol in both male or female LDLRKO and male or female apoEKO mice. Correspondingly, FXR-450 strongly reduced lesion development in female and male ApoEKO mice fed a Western diet. To determine if FXR-450 reduction of lipids and atherosclerotic lesion size is solely mediated by induction of SHP and repression of bile acid synthesis, LDLRKO/SHPKO and ApoEKO/SHPKO were similarly analyzed. In female LDLRKO/SHPKO or female apoEKO/SHPKO, FXR-450 no longer reduced VLDL or LDL cholesterol. Surprisingly, FXR-450 still reduced VLDL and LDL cholesterol in male LDLRKO/SHPKO and male apoEKO/SHPKO. Further FXR-450 significantly reduced lesion development in male apoEKO/SHPKO mice. These results demonstrate activation of FXR has highly beneficial effects on plasma lipids and lesion formation in multiple mouse atherosclerosis models. Further, while induction of SHP appears to be the predominant protective mechanism of FXR activation in female mice, additional mechanisms may play a role, particularly in male mice.

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