Bile Acid Signaling Research Articles

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

BackgroundDietary interventions are implicated in the development of atopic dermatitis, psoriasis, and acne. ObjectiveTo investigate the effect of diet and the bile acid (BA) receptors, such as TGR5 (Takeda G protein receptor 5) and S1PR2 (sphingosine-1-phosphate receptor 2) in the development of dermatitis. MethodsC57BL/6 mice were fed a control diet (CD) or Western diet (WD) since weaning until they were 10 months old followed by analyzing histology, gene expression, and BA profiling. ResultsMice developed dermatitis as they aged and the incidence was higher in females than males. Additionally, WD intake substantially increased the incidence of dermatitis. Cutaneous antimicrobial peptide genesS100A8, S100A9, and Defb4 were reduced in WD-fed mice, but increased when mice developed skin lesions. In addition, Tgr5 and TGR5-regulated Dio2 and Nos3 were reduced in WD intake but induced in dermatitic lesions. Trpa1 and Trpv1, which mediate itch, were also increased in dermatitic lesions. The expression of S1pr2 and genes encoding sphingosine kinases, S1P phosphatases, binding protein, and transporter were all reduced by WD intake but elevated in dermatitic lesions. Furthermore, dermatitis development increased total cutaneous BA with an altered profile, which may change TGR5 and S1PR2 activity. Moreover, supplementation with BA sequestrant cholestyramine reduced epidermal thickening as well as cutaneous inflammatory cytokines. ConclusionIn summary, activation of TGR5 and S1PR2, which regulate itch, keratinocyte proliferation, metabolism, and inflammation, may contribute to WD-exacerbated dermatitis with Th2 and Th17 features. In addition, elevated total BA play a significant role in inducing dermatitis and cutaneous inflammation.

1820-P: Autonomic Tone Is Necessary for Bile Acid-Induced Hepatic Insulin Resistance

Diabetes and obesity cost the American healthcare system in excess of $322 billion dollars annually. Currently, one of the most effective treatments for obesity and metabolic disorders is bariatric surgery. Bariatric surgery leads to almost immediate metabolic benefits, independent of weight loss. Concurrent with the metabolic benefits, an elevation in systemic bile acids is also detected in these patients. Several investigations posit that the rise in systemic bile acids contributes to, or potentially drives, the beneficial outcomes described in these patients; however, the mechanism and direct effects of increased bile acids must be more thoroughly elucidated. Previous studies indicate that not only does the autonomic nervous system impact insulin action, but it also plays a role in bile acid synthesis and secretion. Specifically, studies in humans show that autonomic blockade in insulin resistant subjects leads to improved insulin sensitivity. Furthermore, in rats, a vagotomy results in increased serum bile acids concentrations. Prior data from our group demonstrates that during hyperinsulinemic-euglycemic clamps, increased circulating bile acids induce hepatic insulin resistance, resulting in a decrease in glucose infusion rates (GIR) (10±3 mg/kg/min) compared to control mice (21±4 mg/kg/min). Together these data led to the hypothesis that bile acids signal indirectly via the nervous system to impair hepatic insulin action. To test this hypothesis, autonomic tone was inhibited by infusion of a ganglionic blocker combined with an infusion of an alpha agonist to maintain blood pressure during clamps. In the presence of ganglionic blockade, bile acids do not induce hepatic insulin resistance. Instead, bile acid-treated mice have an increased GIR (66±3 mg/kg/min) compared to control mice (45±5 mg/kg/min). From these data we conclude that the autonomic nervous system is necessary for elevated systemic bile acids to impair insulin action in lean animals. Disclosure K. Syring: None. N.A. Mignemi: None. O.P. McGuinness: None. Funding National Institutes of Health

Impaired Chylomicron Assembly Modifies Hepatic Metabolism Through Bile Acid-Dependent and Transmissible Microbial Adaptations.

The mechanisms by which alterations in intestinal bile acid (BA) metabolism improve systemic glucose tolerance and hepatic metabolic homeostasis are incompletely understood. We examined metabolic adaptations in mice with conditional intestinal deletion of the abetalipoproteinemia (ABL) gene microsomal triglyceride transfer protein (Mttp-IKO), which blocks chylomicron assembly and impairs intestinal lipid transport. Mttp-IKO mice exhibit improved hepatic glucose metabolism and augmented insulin signaling, without weight loss. These adaptations included decreased BA excretion, increased pool size, altered BA composition, and increased fibroblast growth factor 15 production. Mttp-IKO mice absorb fructose normally but are protected against dietary fructose-induced hepatic steatosis, without weight loss or changes in energy expenditure. In addition, Mttp-IKO mice exhibit altered cecal microbial communities, both at baseline and following fructose feeding, including increased abundance of Bacteroides and Lactobacillus genera. Transplantation of cecal microbiota from chow-fed Mttp-IKO mice into antibiotic-treated wild-type recipients conferred transmissible protection against fructose-induced hepatic steatosis in association with a bloom in Akkermansia and increased Clostridium XIVa genera, whose abundance was positively correlated with fecal coprostanol and total neutral sterol excretion in recipient mice. However, antibiotic-treated Mttp-IKO mice were still protected against fructose-induced hepatic steatosis, suggesting that changes in microbiota are not required for this phenotype. Nevertheless, we found increased abundance of fecal Akkermansia from two adult ABL subjects with MTTP mutations compared to their heterozygous parents and within the range noted in six healthy control subjects. Furthermore, Akkermansia abundance across all subjects was positively correlated with fecal coprostanol excretion. Conclusion: The findings collectively suggest multiple adaptive pathways of metabolic regulation following blocked chylomicron assembly, including shifts in BA signaling and altered microbial composition that confer a transmissible phenotype.

Bile acid signaling in renal water regulation.

Emerging evidence has shown that bile acids play important roles in renal physiology and diseases by activating two major receptors, the nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled bile acid receptor-1 (Gpbar1; also known as TGR5). Both FXR and TGR5 have been identified in human and rodent kidneys, where they are deeply involved in renal water handling. In mice, FXR- or TGR5-related gene deficiency has been associated with reduced aquaporin-2 expression accompanied with impaired urinary concentration ability. In this mini-review, we briefly discuss the current understanding of FXR/TGR5 signaling in the kidneys, with a special focus on the regulation of aquaporin-2 expression by bile acids in the collecting ducts and its potential significance in disease conditions.

Roux-en-Y Gastric Bypass Improves Metabolic Conditions in Association with Increased Serum Bile Acids Level and Hepatic Farnesoid X Receptor Expression in a T2DM Rat Model

Roux-en-Y gastric bypass (RYGB) is an effective surgical treatment for type 2 diabetes mellitus (T2DM). The present study aimed to investigate the effects of RYGB on glucose homeostasis, lipid metabolism, and liver morphological adaption, as well as the changes in bile acids signaling and expression of its target regulatory factors involved in gluconeogenesis, lipogenesis, and fatty acid β oxidation. Twenty adult male T2DM rats induced by high-fat diet and a low dose of streptozotocin were randomly divided into sham and RYGB groups. The parameters of body weight, food intake, glucose tolerance, insulin sensitivity, serum lipid profiles, and bile acids level were assessed to evaluate metabolic changes. Liver sections were stained with hematoxylin-eosin (H&E) and oil red O to assess lipid accumulation. The mRNA and protein expression levels of farnesoid X receptor (FXR), small heterodimer partner (SHP), key regulatory factors of gluconeogenesis, lipogenesis, and fatty acid β oxidation (phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-α (PPAR-α)) were determined through RT-PCR and Western blotting, respectively. RYGB induced significant improvements in glucose tolerance and insulin sensitivity, along with weight loss and decreased food intake. RYGB also decreased serum TG, FFAs, and increased bile acids levels. The lipid droplets in the liver were significantly decreased after RYGB. The RYGB group exhibited downregulated mRNA and protein expression levels of PEPCK, G6Pase, and SREBP-1c and upregulated expression of FXR, SHP, and PPAR-α in the liver. RYGB ameliorates glucose and lipid metabolism accompanied by weight loss and calorie restriction. The liver exhibited a marked improvement in lipid accumulation after RYGB. The bile acids level, FXR, and its target transcriptional factor SHP expression were elevated. Meanwhile, our study demonstrated that the increased bile acids-FXR signaling, followed by the reduced hepatic gluconeogenesis, lipogenesis, and increased fatty acid β oxidation may contribute to improved metabolic conditions after RYGB.

Bile acid signaling and control of mitochondrial metabolism

Bile acid signaling and control of mitochondrial metabolism

Bile-ology: from bench to bedside.

Bile acids (BAs) are originally known as detergents essential for the digestion and absorption of lipids. In recent years, extensive research has unveiled new functions of BAs as gut hormones that modulate physiological and pathological processes, including glucose and lipid metabolism, energy expenditure, inflammation, tumorigenesis, cardiovascular disease, and even the central nervous system in addition to cholesterol homeostasis, enterohepatic protection and liver regeneration. BAs are closely linked with gut microbiota which might explain some of their crucial roles in organs. The signaling actions of BAs can also be mediated through specific nuclear receptors and membrane-bound G protein-coupled receptors. Several pharmacological agents or bariatric surgeries have demonstrated efficacious therapeutic effects on metabolic diseases through targeting BA signaling. In this mini-review, we summarize recent advances in bile-ology, focusing on its translational studies.

Bile Acids as Metabolic Regulators and Nutrient Sensors.

Bile acids facilitate nutrient absorption and are endogenous ligands for nuclear receptors that regulate lipid and energy metabolism. The brain-gut-liver axis plays an essential role in maintaining overall glucose, bile acid, and immune homeostasis. Fasting and feeding transitions alter nutrient content in the gut, which influences bile acid composition and pool size. In turn, bile acid signaling controls lipid and glucose use and protection against inflammation. Altered bile acid metabolism resulting from gene mutations, high-fat diets, alcohol, or circadian disruption can contribute to cholestatic and inflammatory diseases, diabetes, and obesity. Bile acids and their derivatives are valuable therapeutic agents for treating these inflammatory metabolic diseases.

The Type 2 Diabetes Susceptibility PROX1 Gene Variants Are Associated with Postprandial Plasma Metabolites Profile in Non-Diabetic Men.

The prospero homeobox 1 (PROX1) gene may show pleiotropic effects on metabolism. We evaluated postprandial metabolic alterations dependently on the rs340874 genotypes, and 28 non-diabetic men were divided into two groups: high-risk (HR)-genotype (CC-genotype carriers, n = 12, 35.3 ± 9.5 years old) and low-risk (LR)-genotype (allele T carriers, n = 16, 36.3 ± 7.0 years old). Subjects participated in two meal-challenge-tests with high-carbohydrate (HC, carbohydrates 89%) and normo-carbohydrate (NC, carbohydrates 45%) meal intake. Fasting and 30, 60, 120, and 180 min after meal intake plasma samples were fingerprinted by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In HR-genotype men, the area under the curve (AUC) of acetylcarnitine levels was higher after the HC-meal [+92%, variable importance in the projection (VIP) = 2.88] and the NC-meal (+55%, VIP = 2.00) intake. After the NC-meal, the HR-risk genotype carriers presented lower AUCs of oxidized fatty acids (−81–66%, VIP = 1.43–3.16) and higher linoleic acid (+80%, VIP = 2.29), while after the HC-meal, they presented lower AUCs of ornithine (−45%, VIP = 1.83), sphingosine (−48%, VIP = 2.78), linoleamide (−45%, VIP = 1.51), and several lysophospholipids (−40–56%, VIP = 1.72–2.16). Moreover, lower AUC (−59%, VIP = 2.43) of taurocholate after the HC-meal and higher (+70%, VIP = 1.42) glycodeoxycholate levels after the NC-meal were observed. Our results revealed differences in postprandial metabolites from inflammatory and oxidative stress pathways, bile acids signaling, and lipid metabolism in PROX1 HR-genotype men. Further investigations of diet–genes interactions by which PROX1 may promote T2DM development are needed.

Neuron‐specific knockout of FXR attenuates the neurological complications of chronic liver disease

Hepatic encephalopathy (HE) describes the neurological deficits that result from liver impairment. Liver disease is associated with an increase of circulating bile acids that can cross the blood brain barrier and activate FXR receptors in neurons. We have previously demonstrated that aberrant bile acid signaling via activation of neuronal FXR contributes to HE pathogenesis in rodent models of acute liver failure. However, a role for FXR‐mediated bile acid signaling in HE due to chronic liver cirrhosis is undefined.MethodsNeuron‐specific FXR knockout mice were generated by crossing Floxed FXR mice (FXRfl) with SNAP‐25 cre recombinase mice. The resulting mice were designated FXRΔneu. C57Bl/6 (WT), FXRfl, and FXRΔneu were treated with carbon tetrachloride (CCl4; 1 ml/kg) by oral gavage twice per week for 12 weeks. Neurobehavioral indices and neuromuscular deficits were assessed by open field test, rotarod, grip strength test and gait analysis. After 12 weeks, tissue was collected and liver damage was assessed by serum chemistry and H&E staining. Total bile acid content was assessed in the cortex and cerebellum using colorimetric assays. The expression of ASBT, FXR, and its downstream effector SHP was assessed by qPCR and immunofluorescence. Microglia activation was assessed by Iba1 immunofluorescence. The expression of proinflammatory cytokines were assessed by qPCR and EIA. In parallel, total bile acids, ASBT and FXR expression were assessed in brain tissue from cirrhotic patients with HE, compared to cirrhotics without HE and age‐ and gender‐matched controls that had been collected and banked by the Australian Brain Bank Network.ResultsTotal bile acid content was elevated in the cortex and cerebellum in CCl4‐treated WT mice and in cirrhotic patients with HE, compared to cirrhotics without HE and non‐liver impaired controls. Furthermore, ASBT, FXR and SHP expression were increased in the frontal cortex of mice and humans with HE, but not in non‐HE control samples. WT and FXRfl mice treated with CCl4 had significant deficits observed in every neurobehavioral and neuromuscular test performed, as well as marked microglia activation and increased proinflammatory cytokine expression compared to vehicle‐treated mice. These neurological deficits and neuroinflammation were attenuated in FXRΔneu mice after CCl4 treatment, even though liver damage was comparable in all genotypes of mice used.ConclusionsTaken together, these data indicate that neuronal expression of FXR plays an important role in the development of HE. Specific targeting of FXR activation in the brain may prove fruitful in the development of novel therapeutics for the management of HE.Support or Funding InformationThis study was funded by NIH R01 awards (DK082435 and DK112803) and a VA Merit award (BX002638) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service to Dr. DeMorrow. This study was also funded by a VA Career Development award (BX003486) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service to Dr. McMillin.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

THU-007-Absence of BSEP (ABCB11) protects MDR2 (ABCB4) KO mice from cholestatic liver and bile duct injury through anti-inflammatory bile acid composition and signaling

THU-007-Absence of BSEP (ABCB11) protects MDR2 (ABCB4) KO mice from cholestatic liver and bile duct injury through anti-inflammatory bile acid composition and signaling

Keystone Species in the Pathogenic Process of NAFLD

BackgroundThe role of gut microbiome in the pathogenic process of NAFLD has been increasingly recognized. However, the keystone species in the gut of NAFLD, the critical factor(s) in maintaining the stability of the entire gut microbiome, has not been reported.MethodSparCC method was used to construct the microbial interaction ecosystem of human gut microbiome in healthy condition. PageRank algorithm was used to evaluate the importance of each bacterial species in healthy gut micro‐ecology system. Subsequently, the keystone species required for maintaining the stability of gut micro‐ecological system was identified on the basis of network stability assessment. Finally, the keystone species specific for NAFLD was determined by the quantitative analysis of gut microbiome between NAFLD patients and healthy people. And the relevant OTUs were annotated at species‐level based on phylogenetic trees. Furthermore, the same keystone species identification analysis was also conducted in NAFLD rats induced by high‐fat diet.ResultsHere we reconstructed the microbial interaction ecosystem of healthy human gut microbiome, consisting of 61 bacterial species and 90 pairwise interactions. Wherein, Bacteroides ovatus, Faecalibacterium prausnitzii, Barnesiella intestinihominis, Odoribacter splanchnicus, Roseburia faecis, Eubacterium ventriosum, Clostridium leptum were the seven keystone species that maintained the stability of the gut micro‐ecological system. The results of quantitative analysis indicated that the abundance of B. intestinihominis, E. ventriosum and C. leptum decreased significantly in the gut of NAFLD patients, and they were identified as the keystone species specific for NAFLD. These species could participate in the initiation and development of NAFLD by regulating the metabolic process of bile acid signaling and the activity of inflammasome. In addition, similar results were observed in the gut microbiome of NAFLD rats.ConclusionThis research identifies the keystone species specific for NAFLD, and highlights a novel target for the precise prevention and treatment of NAFLD based on gut microbiome. Importantly, our strategy for the identification of the keystone species can be extended to other ecological systems.Support or Funding InformationThis work was supported by National Natural Science Foundation of China 81770571 (to LZ), 81774152(to RZ), 41530105 (to RZ).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Changes in Bile Acid Metabolism, Transport, and Signaling as Central Drivers for Metabolic Improvements After Bariatric Surgery.

We review current evidence regarding changes in bile acid (BA) metabolism, transport, and signaling after bariatric surgery and how these might bolster fat mass loss and energy expenditure to promote improvements in type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). The two most common bariatric techniques, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), increase the size and alter the composition of the circulating BA pool that may then impact energy metabolism through altered activities of BA targets in the many tissues perfused by systemic blood. Recent reports in human patients indicate that gene expression of the major BA target, the farnesoid X receptor (FXR), is increased in the liver but decreased in the small intestine after RYGB. In contrast, intestinal expression of the transmembrane G protein-coupled BA receptor (TGR5) is upregulated after surgery. Despite these apparent conflicting changes in receptor transcription, changes in BAs after both RYGB and VSG are associated with elevated postprandial systemic levels of fibroblast growth factor 19 (from FXR activation) and glucagon-like peptide 1 (from TGR5 activation). These signaling activities are presumed to support fat mass loss and related metabolic benefits of bariatric surgery, and this supposition is in agreement with findings from rodent models of RYGB and VSG. However, inter-species differences in BA physiology limit direct translation and mechanistic understanding of how changes in individual BA species contribute to post-operative improvements of T2D and NAFLD in humans. Thus, details of all these changes and their influences on BAs' biological actions are still under scrutiny. Changes in BA physiology and receptor activities after RYGB and VSG likely support weight loss and promote sustained metabolic improvements.

Anti-inflammatory, anti-oxidative stress and novel therapeutic targets for cholestatic liver injury.

Cholestasis is a pathological process in which bile drainage is poor for a variety of reasons. Many studies have shown that cholestatic liver injury is a neutrophil-mediated inflammatory response, and oxidative stress induced by neutrophils is the main mechanism of liver cell death. The literature summarizes the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the oxidative stress damage produced by neutrophil activation, summarizes the latest research progress. Sphingosine-1-phosphate receptor (S1PR) is a potential therapeutic target for cholestasis that reduces neutrophil aggregation without inhibiting systemic immune status. Early growth response factor 1 (Egr-1) may play a central role in the inflammation induced by cholestasis, and it is also a potential therapeutic target to inhibit the inflammation induced by cholestasis. Strengthening the antioxidant system of hepatocytes to cope with oxidative stress of neutrophils is a feasible treatment for cholestatic liver injury.

Systemic bile acids induce insulin resistance in a TGR5-independent manner.

Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.

Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1PR2, ERK and SF-1.

Background and AimsBile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor (FXR), the G protein‐coupled bile acid receptor (TGR5) and the sphingosine‐1‐phosphate receptor 2 (S1PR2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production.Methods FXR and TGR5 knockout mice and controls were subjected to common bile duct ligation (CBDL) or chenodeoxycholic acid (CDCA) feeding to model cholestasis. Human adrenocortical H295R cells were challenged with bile acids for mechanistic studies.ResultsWe found that CBDL and CDCA feeding increased the levels of corticosterone, the rodent equivalent to human cortisol and mRNA and protein levels of steroidogenesis‐related enzymes in adrenals independent of FXR and TGR5. Taurine‐conjugated CDCA (TCDCA) significantly stimulated cortisol secretion, phosphorylation of extracellular signal‐regulated kinase (ERK) and expression of steroidogenesis‐related genes in human adrenocortical H295R cells. FXR and TGR5 agonists failed to induce cortisol secretion in H295R cells. S1PR2 inhibition significantly abolished TCDCA‐induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis‐related genes in H295R cells. Likewise, siRNA S1PR2 treatment reduced the phosphorylation of ERK and cortisol secretion. Steroidogenic factor‐1 (SF‐1) transactivation activity was increased upon TCDCA treatment suggesting that bile acid signalling is linked to SF‐1. Treatment with SF‐1 inverse agonist AC45594 also reduced TCDCA‐induced steroidogenesis.ConclusionsOur findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR2‐ERK‐SF‐1 signalling pathway.

P082 Xenobiotic nuclear receptors: linking bile acid signalling to alterations in CYP3A4 metabolism in Crohn's disease

P082 Xenobiotic nuclear receptors: linking bile acid signalling to alterations in CYP3A4 metabolism in Crohn's disease

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets.

Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease.

Bile Acid-Activated Receptors: A Review on FXR and Other Nuclear Receptors.

Nuclear receptors (NRs) are ligand-dependent transcription factors that are involved in various biological processes including metabolism, reproduction, and development. Upon activation by their ligands, NRs bind to their specific DNA elements, exerting their biological functions by regulating their target gene expression. Bile acids are detergent-like molecules that are synthesized in the liver. They not only function as a facilitator for the digestion of lipids and fat-soluble vitamins but also serve as signaling molecules for several nuclear receptors to regulate diverse biological processes including lipid, glucose, and energy metabolism, detoxification and drug metabolism, liver regeneration, and cancer. The nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D receptor (VDR), and small heterodimer partner (SHP) constitute an integral part of the bile acid signaling. This chapter reviews the role of the NRs in bile acid homeostasis, highlighting the regulatory functions of the NRs in lipid and glucose metabolism in addition to bile acid metabolism.

Evidence of functional bile acid signaling pathways in adipocytes

Background and aimBile acids (BA) are increasingly recognized as pleiotropic and hormone-like signaling molecules with metabolic and endocrine functions. However, the role of BA in white adipocyte physiology remains somewhat obscure. It was the aim to investigate the BA receptors (FXR, TGR5) and FGFR1 (Fibroblast growth factor receptor 1) as well as Bsep (bile salt export pump) in white adipocytes and in murine and human adipose tissue (AT) and to investigate effects of different BA species in adipocyte physiology. Patients, material and methodsReceptor mRNA expression was quantified by real-time PCR in mice, humans and during 3T3-L1 pre-adipocyte differentiation. Adipokines were measured by ELISA upon stimulation by several BA. Effects of BA on TNF- and LPS-induced MCP-1 secretion and lipolysis were analyzed. TNF-induced lipolysis was investigated by glycerol assay. ResultsThe present data provide for the first time a detailed expression profile of FXR, TGR5, FGFR1, and Bsep during adipocyte differentiation and in murine and human AT. FGFR1 expression is upregulated in adipose tissue of LPS-injected animals. Several BA regulate secretion of adipokines such as adiponectin and resistin differentially. Importantly, TNF- and LPS-induced MCP-1 release from adipocytes as well as TNF-induced lipolysis can be antagonized by cholic acid (CA) and deoxycholic acid (DCA). ConclusionsThe present data provide evidence of functional BA signaling pathways in adipocytes and argue for certain MCP-1 related anti-inflammatory effects of BA in TNF- and LPS-induced inflammation, whereas pro-inflammatory resistin is induced by CA and glycocholic acid (GCA). Systemic bile acids might represent a hormonal network regulating white adipocyte physiology including lipolysis.