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Intestinal bile acid receptors are key regulators of glucose homeostasis

Published online by Cambridge University Press:  16 November 2017

Mohamed-Sami Trabelsi*
Affiliation:
Institut National de la Santé et de la Recherche Médicale, U1048, Université Paul Sabatier, UPS, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), CHU Rangueil, 1 Avenue Jean Poulhès, BP84225, 31432 Toulouse, Cedex 4, France
Sophie Lestavel
Affiliation:
University Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France
Bart Staels
Affiliation:
University Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France
Xavier Collet
Affiliation:
Institut National de la Santé et de la Recherche Médicale, U1048, Université Paul Sabatier, UPS, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), CHU Rangueil, 1 Avenue Jean Poulhès, BP84225, 31432 Toulouse, Cedex 4, France
*
*Corresponding author: M.-S. Trabelsi, email sami.trabelsi@inserm.fr
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Abstract

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.

Type
Conference on ‘New technology in nutrition research and practice’
Copyright
Copyright © The Authors 2016 

Importance of bile acids and regulation of their metabolism

Bile acids, synthesised from cholesterol by periveinous hepatocytes, contain a twenty-four-carbon steroid core and a side carboxyl chain. Due to hydroxyl groups on the steroid core, bile acids are amphipathic molecules. The position and the number of hydroxyl groups on the steroid group allow the classification of the different bile acids. Bile acid synthesis is driven by multiple step reactions divided into two pathways. The classical (or neutral) pathway depends on cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1), which catalyse hydroxylation in position α on C7 and C12, respectively, of the steroid core thus generating cholic acid (CA), chenodeoxycholic acid (CDCA, predominant in human) and muricholic acids (MCA, predominant in rodents). Schematically, CYP7A1 activity determines the bile acid pool size, whereas CYP8B1 determines the CA:CDCA or CA:MCA ratios thus defining the bile acid pool composition( Reference Pandak, Bohdan and Franklund 1 , Reference Li-Hawkins, Gåfvels and Olin 2 ). CYP7A1 knockout (KO) mice display only a 66 % reduction in bile acid pool size, pointing to an alternative (or acidic) pathway for bile acid synthesis( Reference Schwarz, Russell and Dietschy 3 ). This pathway depends on the activity of sterol 27-hydroxylase (CYP27A1) and oxysterol-7α-hydroxylase (CYP7B1). Bile acids, synthesised in the liver by both the classical and the alternative pathways, are the primary bile acids. They are then conjugated to glycine (predominant conjugation in human subjects) and taurine (predominant conjugation in mice) at C24 position by the bile acid coenzyme A:aminoacid N-acyl transferase, thus increasing their hydrophilicity and inhibiting their hepatic reflux.

Enterohepatic cycle of bile acids and their importance in intestinal postprandial lipid absorption

Once synthesised, bile acids are secreted into the canalicular space between hepatocytes and reach gallbladder (Fig. 1). Then bile acids are mixed with potassium and sodium ions thereby forming bile salts. The arrival of a meal in the proximal duodenum induces the secretion of cholecystokinin by enteroendocrine I-cells, which subsequently binds to cholecystokinin A receptors on cholangiocytes, induces gallbladder contraction and bile release into the duodenal lumen. There, bile acids facilitate dietary lipid and fat-soluble vitamin absorption and transport by forming, together with phospholipids, TAG, lipid-soluble vitamins and cholesterol, the postprandial mixed micelles. Indeed, it has been shown using the human differentiated Caco-2 cell line, a model frequently used to study apical-to-basolateral lipid transport, that there is no transport of postprandial micelles without taurocholate (TCA)( Reference Luchoomun and Hussain 4 ). Bile acids are not absorbed and continue until the distal intestine (i.e. ileum) where they are re-absorbed involving the apical sodium-dependent bile salt transporter, and the basolateral heterodimer organic solute transporter α/β (OSTα/OSTβ) and reach portal blood (Fig. 1). From the portal circulation, bile acids are taken up by the liver via different transporters belonging to the organic anion transporting polypeptide family( Reference Hagenbuch and Meier 5 ) or via the sodium-TCA cotransporting polypeptide (NTCP/SLC10A1) thus closing their enterohepatic cycle. In human subjects, and depending on when the measure was made but also on the regimen, this cycle occurs six to twelve times daily thus limiting bile acid faecal loss( Reference Mazuy, Helleboid and Staels 6 , Reference Prawitt, Caron and Staels 7 ). It is reported that 95 % of bile acids are re-absorbed in the distal ileum and 5 % of bile acids arrive in the colon( Reference de Aguiar Vallim, Tarling and Edwards 8 ). In the ileum and mainly in the colon, primary bile acids are deconjugated and de-hydroxylated by bacteria belonging to the gut microbiota thus generating secondary bile acids. Indeed, some bacteria mainly belonging to the Clostridiales and Bacteroidales orders display bile salt hydrolase activity transforming (tauro- and/or glyco-) CA and (tauro- and/or glyco-) CDCA acids into deoxycholic acid (DCA) and lithocholic acids (LCA), respectively( Reference Dey, Wagner and Blanton 9 ). These biochemical reactions increase colonic bile acid re-absorption.

Fig. 1. (Colour online) Enterohepatic cycle of bile acids. Bile acids are produced from cholesterol in the liver. In the fasted state, bile acids are stored in the gallbladder. After meal ingestion, bile acids are expulsed in the intestinal lumen where they emulsify dietary fat. In the ileum, 95 % of bile acids are reabsorbed by the apical sodium-dependent bile salt transporter (ASBT) and basolateral heterodimer organic solute transporter α/β (OSTα/OSTβ). Through the portal circulation, bile acids return to the liver where, by their binding to FXR, they decrease gene expression of the rate-limiting enzymes in bile acid synthesis, i.e. Cyp7a1 and Cyp8b1. In enterocytes, the activated farnesoid X receptor (FXR) increases Fgf15/19 and Shp gene expression thus participating to bile acid metabolism regulation. In L-cells, bile acids bind and activate G-protein-coupled bile acid receptor 1 (TGR5) leading to the secretion of the incretin glucagon-like peptide 1 (GLP-1). By contrast, the activated FXR in L-cells decreases glucose-induced GLP-1 secretion.

Regulation of bile acid metabolism: the role of bile acid receptors

At high concentrations bile acids are cytotoxic molecules. The organism has developed numerous regulatory mechanisms to avoid their overproduction and their accumulation in organs( Reference Rolo, Palmeira and Holy 10 Reference Perez and Briz 12 ). These mechanisms, driven by a negative feedback by bile acids themselves, involve both transmembrane and nuclear receptors (NR). Among them, the membrane G-protein-coupled bile acid receptor 1 (TGR5) and the  NR pregnane X receptor and farnesoid X receptor (FXR) participate to alleviate hepatic and intestinal bile acid overload (Fig. 1). The most studied receptors in term of bile acid and glucose metabolism are TGR5 and FXR, we will only focus this review on these two receptors.

TGR5 is a membrane receptor which is activated by oleanolic acid, a triterpenoid molecule, and bile acids (affinity for TGR5: tauro-LCA = LCA > DCA > CDCA = CA)( Reference Prawitt and Staels 13 ). First described as a regulator of cytokine production in a human monocyte cell line( Reference Kawamata, Fujii and Hosoya 14 ), TGR5 is expressed in Küpffer cells, cholangiocytes, adipocytes, myocytes and enteroendocrine cells( Reference Maruyama, Tanaka and Suzuki 15 Reference Briere, Ruan and Cheng 17 ). It has been reported that whole body TGR5 KO mice have a decreased bile acid pool size( Reference Maruyama, Tanaka and Suzuki 15 , Reference Harach, Pols and Nomura 18 , Reference Li, Holmstrom and Kir 19 ). These animals also display more TCA and less tauro-beta MCA and have decreased expression of Cyp7b1 and Cyp27a1 gene expression than wild-type (WT) animals( Reference Donepudi, Boehme and Li 20 ). Incubation of murine hepatocytes with culture media from TGR5-activated macrophages decreases Cyp7a1 gene expression( Reference Lou, Ma and Fu 21 ), thus highlighting a possible paracrine function of TGR5 in Küpffer cells in hepatic bile acid synthesis regulation. Moreover, the gallbladder is the organ with the highest TGR5 expression levels( Reference Briere, Ruan and Cheng 17 ). TGR5 agonists stimulate gallbladder filling by a mechanism involving cAMP and muscle relaxation( Reference Briere, Ruan and Cheng 17 , Reference Li, Holmstrom and Kir 19 ). Finally, TGR5 is also expressed in the colon in enterochromaffin cells and myenteric neurons where its activation decreases colonic contractility and motility through a 5-hydroxytryptamin/calcitonin-gene-related peptide pathway, a well-known regulatory mechanism of intestinal peristaltism( Reference Alemi, Poole and Chiu 22 Reference Grider, Piland and Gulick 25 ). By increasing the delay before defecation, this mechanism can participate to better intestinal bile acid reabsorption but further studies are needed to fully decipher the role of TGR5 in bile acid metabolism.

Bile acids also regulate their own synthesis through binding and activation of the nuclear bile acid receptor FXR, firstly identified in 1995 in rodents( Reference Seol, Choi and Moore 26 , Reference Forman, Goode and Chen 27 ) as a receptor for farnesol( Reference Wang, Chen and Hollister 28 ). In eukaryotes, the NR superfamily is the largest transcription factor family. Forty-nine NR have been identified so far( Reference Mangelsdorf, Thummel and Beato 29 ). FXR is encoded by the NR1H4 gene. Almost all NR share a common structure with five functional domains. As the other NR, the N-terminal domain of FXR is constituted by a ligand-independent activation site called activated function-1 and a DNA-binding domain. These regions are separated from the ligand-binding domain and the ligand-dependent activation site (activated function-2) by a hinge region. Due to alternative splicing and the utilisation of different promoters, four FXR isoforms (FXRα1–4) have been reported (for review( Reference Prawitt, Caron and Staels 7 )). The most transcriptionally active FXR isoforms are FXRα2 and FXRα4 that differ from FXRα1 and FXRα3, respectively, by an introduction of four extra amino acids in the hinge region( Reference Zhang, Kast-Woelbern and Edwards 30 ). FXR is highly expressed in the intestine, liver and kidney and at lower levels in adipose tissue and pancreas. Primary bile acids are the most potent activators of FXRα (called thereafter FXR; affinity for FXR: CDCA > TCA > DCA = tauro-LCA; for review( Reference Prawitt and Staels 13 )). Moreover,  tauro-alpha MCA, tauro-beta MCA and ursodeoxycholic acid have been identified recently as FXR antagonists( Reference Hu, Bonde and Eggertsen 31 Reference Campana, Pasini and Roda 33 ). The development early in the 21st century of whole-body FXR KO mice highlighted the crucial role of FXR in energy homeostasis and more specifically in bile acid metabolism( Reference Sinal, Tohkin and Miyata 34 ). Indeed, FXR KO mice display an increase in plasma bile acid, as well as TAG and cholesterol levels compared with WT littermates. Once activated by postprandial bile acids, hepatic FXR increases Nr0b2 gene expression (small heterodimer partner), an orphan NR with co-repressor activities, which decreases Cyp7a1 and Cyp8b1 gene expression by direct interaction with liver receptor homologue-1) and the recruitment of corepressors thus decreasing bile acid synthesis( Reference Lu, Makishima and Repa 35 , Reference Sanyal, Båvner and Haroniti 36 ) (Fig. 1). Hepatic activated FXR also decreases Cyp7b1 and Ntcp and increases Bsep, Ostα, Ostβ and Mdr3 (multi drug resistance 3) gene expression thus enhancing hepatic bile acid drain (for review( Reference Lefebvre, Cariou and Lien 37 )). In the intestine, FXR activation up-regulates Ibabp and Ostα/Ostβ and decreases apical sodium-dependent bile salt transporter gene expression thus enhancing the enteroportal circulation of bile acids( Reference Chen, Ma and Dawson 38 Reference Lee, Zhang and Lee 41 ). In enterocytes, FXR upregulates the expression and the secretion in the portal blood of fibroblast growth factor (FGF; 15 in mice, 19 in human subjects)( Reference Markan and Potthoff 42 ). Through a pathway not yet fully identified involving β-Klotho, FGF15/19 activates hepatic FGFR4 and decreases Cyp7a1 gene expression in the liver( Reference Owen, Mangelsdorf and Kliewer 43 ). Thus, FXR in both hepatocytes and enterocytes controls bile acid metabolism and decreases their cellular toxicity (Fig. 1).

Enteroendocrine cells, glucose and bile acid receptors

Enteroendocrine cells

Even if enteroendocrine cells represent only 1 % of the total intestinal epithelial cells, the length of the intestine makes it the largest endocrine organ. Based on the peptide they secrete and on their expression profile all along the intestine, at least thirteen different enteroendocrine cell types have been identified. Among them, enteroendocrine K- and L-cells secrete the incretins glucose-insulinotropic polypeptide (IP) and glucagon-like peptide (GLP)-1. The incretin effect is based on the observation that oral glucose administration induces a more pronounced insulin secretion than an isoglycaemic intraveinous injection. The enteroendocrine L-cells are present all along the upper and the lower intestine following a cephalocaudal gradient with a maximum abundance in the colon. The proglucagon gene, the same gene that produces pancreatic glucagon, encodes GLP-1. After transcription and translation into proglucagon, the action of prohormone convertase 1/3 in L-cells leads to GLP-1, GLP-2, oxyntomodulin and IP2, whereas the action of prohormone convertase 2 in pancreatic α-cells leads to glucagon, glicentin-related polypeptide, IP1 and major proglucagon fragment (for review( Reference Baggio and Drucker 44 )). In L-cells, the main bioactivity on glucose metabolism is linked to GLP-1. Indeed, in the pancreas, GLP-1 potentiates glucose-induced insulin secretion thus increasing insulin sensitivity of key metabolic organs such as skeletal muscle, adipose tissue and the liver. GLP-1 also inhibits gastric emptying, increases satiety and cardiac function. In blood, GLP-1 half-life is about 1·5–5 min due to a rapid degradation by dipeptidyl peptidase 4. Therapeutic strategies leading to more stable GLP-1 or to a lower GLP-1 degradation have been developed (for review( Reference Baggio and Drucker 44 )). These drugs are the non-hydrolysable GLP-1 mimetics and  dipeptidyl peptidase 4 inhibitors that are successfully used to treat type 2 diabetic patients. Another strategy to increase GLP-1 activity would be to increase its endogenous production and secretion by L-cells.

Glucose is a regulator of glucagon-like peptide 1 production and secretion

Many diet-derived metabolites such as oleoylethanolamine, n-3 PUFA, the SCFA butyrate and propionate, glutamine and L-ornithine drive GLP-1 secretion mainly through binding and activation of diverse G-protein-coupled receptors (for review( Reference Ward 45 )). Glucose also enhances GLP-1 biosynthesis and secretion. Two distinct mechanisms both leading to an increase of intracellular calcium concentrations and membrane fusion of GLP-1 containing vesicles are involved in glucose-induced GLP-1 secretion. The first mechanism involves the sodium-glucose cotransporter 1 where the entry of two sodium ions, concomitantly with one molecule of glucose, induces a difference of potential leading to the opening of a voltage-dependent calcium channel( Reference Parker, Adriaenssens and Rogers 46 , Reference Reimann, Habib and Tolhurst 47 ). Although this mechanism seems to be the driving force for glucose-induced GLP-1 secretion( Reference Gorboulev, Schürmann and Vallon 48 ), a second mechanism identified only recently and involving GLUT2-mediated intracellular glucose catabolism through glycolysis pathway has been described( Reference Kuhre, Frost and Svendsen 49 ). At high extracellular glucose concentrations, the increase in intracellular glucose levels to millimolar range induces glucose catabolism into pyruvate through the glycolysis pathway. Then pyruvate is decarboxylated and conjugated to CoA to form acyl-CoA. By entering in the mitochondrial citrate cycle, acyl-CoA increases the ATP:ADP ratio, which leads to the closure of potassium ATP-dependent channels. The subsequent accumulation of potassium in the intracellular space leads to membrane depolarisation thus opening voltage-dependent calcium channels and the intracellular accumulation of calcium leads to GLP-1 vesicle release( Reference Ward 45 , Reference Kuhre, Frost and Svendsen 49 ). A few years ago glucose was identified as a proglucagon gene expression enhancer( Reference Daoudi, Hennuyer and Borland 50 ). Recently, a role for the carbohydrate responsive element-binding protein (ChREBP) in the glucose-mediated proglucagon gene increase has been proposed( Reference Trabelsi, Daoudi and Prawitt 51 ). ChREBP is a transcription factor activated by glucose metabolites and is highly expressed in enteroendocrine L-cells( Reference Habib, Richards and Cairns 52 , Reference Filhoulaud, Guilmeau and Dentin 53 ). We have shown that glucose increases proglucagon gene expression in small interference (si)Ctrl, but not in siChREBP enteroendocrine murine L-cells( Reference Trabelsi, Daoudi and Prawitt 51 ). Moreover, incubation with lactate or 2-deoxyglucose, a non-metabolisable glucose analogue, does not increase proglucagon gene expression. Thus, both ChREBP and glucose catabolism are mandatory for the observed glucose-mediated proglucagon gene expression( Reference Trabelsi, Daoudi and Prawitt 51 ). However, further studies are needed to fully address the mechanisms behind this ChREBP-dependent glucose-mediated proglucagon gene increase (Fig. 2).

Fig. 2. (Colour online) Activation of bile acid receptors in L-cells modulates glucagon-like peptide-1 (GLP-1) production and secretion. Activation of L-cell G-protein-coupled bile acid receptor 1 (TGR5) increases intracellular cAMP levels, thus leading to an increase in both GLP-1 production and secretion through the protein kinase (PK) A/cAMP responsive elements binding protein pathway and exchange protein directly activated by cAMP (EPAC2)/diacylglycerol (DAG)/PKCζ and EPAC2/phospholipase C (PLCε)/insulinotropic polypeptide (IP)3 pathways, respectively. Activation of L-cell farnesoid X receptor (FXR) in the presence of glucose decreases the glycolysis pathway, thus leading to lower intracellular ATP levels. This decrease is associated with lower levels of GLP-1. Moreover, FXR is in the same complex as carbohydrate responsive element-binding protein (ChREBP) and decreases glucose-induced proglucagon gene expression. The bile acid sequestrant (BAS) colesevelam, by inhibiting FXR activation, prevents these decreases. Furthermore, bile acid in complexes with BAS are still able to activate TGR5, thus further increasing L-cell GLP-1 secretion.

Bile acids are regulators of glucagon-like peptide 1 production and secretion via the bile acid receptors G-protein-coupled bile acid receptor 1 and farnesoid X receptor

As shown for glucose, bile acids also modulate both GLP-1 secretion and proglucagon gene expression. TGR5 is expressed all along the intestine with the maximum levels in the colon, where the enteroendocrine L-cells are predominant( Reference Harach, Pols and Nomura 18 ). In experiments on L-cells isolated using the transgenic GLU-Venus mouse model, it has been shown that TGR5 expression is mainly restricted to enteroendocrine L-cells( Reference Reimann, Habib and Tolhurst 47 ). Binding of bile acids to TGR5 in L-cells dissociates the Gαs subunit of the heterotrimeric protein from the Gβ/γ subunits. Thus, activated Gαs activates adenylate cyclase that converts ATP into cAMP. After binding of cAMP to the two regulatory subunits of protein kinase A, the catalytic subunits of protein kinase A are dissociated and shuttle to the nucleus. There, protein kinase A phosphorylates and activates cAMP responsive elements binding protein, which in turn binds to cAMP responsive elements in the promoter of target genes, including proglucagon, thus regulating their expression( Reference Harach, Pols and Nomura 18 , Reference Vallim and Edwards 54 , Reference Thomas, Gioiello and Noriega 55 ) (Fig. 2). cAMP produced upon TGR5 activation also triggers GLP-1 secretion through the EPAC2/phospholipase Cε/IP3 and EPAC2/diacylglycerol/protein kinase Cζ pathways( Reference Harach, Pols and Nomura 18 , Reference Thomas, Gioiello and Noriega 55 Reference Bala, Rajagopal and Kumar 57 ) (EPAC, exchange protein directly activated by cAMP) (Fig. 2). Very recently, it has been shown that bile acid-induced GLP-1 secretion is mediated mostly through TGR5 located at the basolateral side of L-cells( Reference Brighton, Rievaj and Kuhre 58 ).

Using L-cells sorted by fluorescence-activated cell sorting from GLU-Venus mice, it has been shown that FXR is also expressed in L-cells( Reference Trabelsi, Daoudi and Prawitt 51 ). Moreover, FXR mRNA levels are higher in L-cells than in non-L-cells. In fresh human jejunal biopsies, GLP-1 immunoreactive cells are also immunoreactive for FXR showing that FXR is expressed in human L-cells. In both human subjects and mice, FXR activation by either bile acids or the specific FXR agonist GW4064 decreases GLP-1 production. More precisely, L-cell-activated FXR is in the same protein complexes containing ChREBP and inhibits glucose-induced ChREBP-mediated proglucagon gene expression as shown by using siChREBP transfected cells and a non-metabolisable glucose analogue. Moreover, FXR activation also decreases glucose-induced GLP-1 secretion. Specifically, in glucose-containing media, FXR activation overall decreases the glycolysis pathway at the gene expression level, lowers intracellular ATP levels and finally lowers glucose-induced GLP-1 release. KCl-induced GLP-1 secretion is not altered by FXR activation, showing the glucose dependency of FXR action on GLP-1 secretion. This glucose dependency is more specifically due to the glycolysis pathway since the glucose-induced GLP-1 secretion is not decreased after GW4064 treatment of murine biopsies challenged with a GLUT-2 inhibitor. These results show that FXR activation decreases both proglucagon gene expression and GLP-1 secretion by interfering with pathways activated by glucose( Reference Trabelsi, Daoudi and Prawitt 51 ) (Fig. 2). The importance of this FXR–GLP-1 pathway as a potential therapeutic target will be discussed later.

In a pathophysiological context of obesity and type 2 diabetes, intestinal bile acid receptors are regulators of energy and glucose homeostasis

Obese and type 2 diabetic patients have altered bile acid metabolism

Obesity and type 2 diabetes (T2D) have been shown to have reached pandemic levels in industrial countries. The WHO estimated 600 million obese and 422 million diabetic individuals in 2014( 59 , 60 ). T2D is characterised by fasting hyperglycaemia and insulin resistance which participate together with hypertriglyceridaemia, hypercholesterolaemia, abdominal obesity and hypertension, in the so-called metabolic syndrome( Reference Huang 61 ). Early and recent studies highlight a disrupted bile acid pool size and/or composition in T2D( Reference Bennion and Grundy 62 Reference Sonne, van Nierop and Kulik 66 ). Patients with uncontrolled T2D have an increase in bile acid pool size, which disappears after insulin treatment( Reference Bennion and Grundy 62 ). Other studies show no differences in bile acid pool size between uncontrolled and insulin treated T2D patients but a change in bile acid pool composition with an increase in the proportion of the secondary bile acid DCA( Reference Abrams, Ginsberg and Grundy 63 , Reference Brufau, Stellaard and Prado 64 ). Another study shows that an increase of plasma DCA occurs together with a decrease in plasma CA( Reference Suhre, Meisinger and Döring 65 ). Very recently, it has been reported in human subjects that the amplitude in plasmatic postprandial bile acid levels is positively correlated with meal fat content. Moreover, and when compared to age-, sex- and BMI-matched normoglycemic subjects, T2D patients display an increase in total plasma bile acids, mainly due to increases in glycine conjugated bile acids, in DCA and in ursodeoxycholic acid during both oral glucose- and meal tolerance tests( Reference Sonne, van Nierop and Kulik 66 ). Finally, 12α-hydroxylated bile acids are negatively associated with insulin sensitivity( Reference Haeusler, Astiarraga and Camastra 67 ). Even though some discrepancies exist, these studies clearly support the notion of change in bile acid metabolism in T2D. Moreover, in rats fed a high-fat diet, bile diversion to distal intestine improved glucose tolerance( Reference Goncalves, Barataud and De Vadder 68 ). Such an improvement is also observed in mice after bile diversion( Reference Flynn, Albaugh and Cai 69 , Reference Pierre, Martinez and Ye 70 ) or in mice after ileal interposition, which bypasses bile acid cycling( Reference Kohli, Kirby and Setchell 71 ). An increase in GLP-1 secretion is one of the mechanisms evocated to explain these beneficial effects. Furthermore, in healthy subjects, TCA administration stimulates the secretion of GLP-1 by enteroendocrine L-cells and increases fullness sensation( Reference Wu, Bound and Standfield 72 ). The same year, another team has shown that intrarectal TCA administration increases GLP-1 secretion and decreases blood glucose without hypoglycaemia in obese T2D patients( Reference Adrian, Gariballa and Parekh 73 ). A better understanding of how bile acids act as signalling molecules through TGR5 and FXR can thus be of interest to develop specific molecules to treat T2D.

It has been difficult to appreciate the exact contribution of each bile acid receptor to energy homeostasis since bile acids are ligands for both TGR5 and FXR. The development of specific synthetic (such as GW4064) or semi-synthetic (such as obeticholic acid (INT-747) and fexaramine) FXR agonists, as well as specific TGR5 agonists (such as INT-777), allow the study of the impact of each bile acid receptor activation to energy homeostasis. Moreover, the development of whole body as well as organ-specific FXR and TGR5 KO animals allows further discrimination of the relative contribution of each bile acid receptor in a specific tissue on glucose metabolism in the pathophysiological context of obesity and T2D (for review( Reference Luchoomun and Hussain 4 , Reference Hagenbuch and Meier 5 , Reference Lefebvre, Cariou and Lien 37 )).

G-protein-coupled bile acid receptor 1

TGR5 activation is important in energy metabolism regulation via its capacity to increase energy expenditure and to promote GLP-1 production. Indeed, TGR5 is expressed in brown adipose tissue and skeletal muscle where, through the cAMP/deiodinase 2 pathway, it catalyses the conversion of inactive prohormone thyroxine to active 3,5,3′-tri-iodothyronine( Reference Watanabe, Houten and Mataki 16 , Reference Bianco, Maia and da Silva 74 ). This hormone thus enhances brown adipose tissue lipolysis and increases thermogenesis( Reference Watanabe, Houten and Mataki 16 ). TGR5 is also involved in lipid metabolism regulation. Whereas both male and female TGR5 KO mice display similar body weight compared to their WT littermates when fed a high-fat diet( Reference Maruyama, Tanaka and Suzuki 15 , Reference Vassileva, Hu and Hoos 75 ), TGR5 KO female animals have less cholesterol in VLDL, LDL and HDL lipoprotein fractions( Reference Vassileva, Hu and Hoos 75 ). These mice also display less TAG in VLDL fraction than TGR5 WT mice( Reference Vassileva, Hu and Hoos 75 ). Very recently, it has been shown by Donepudi et al.( Reference Donepudi, Boehme and Li 20 ) that TGR5 KO mice are protected against fasting-induced steatosis. Thomas et al.( Reference Thomas, Gioiello and Noriega 55 ) have shown that high-fat-fed mice containing a constitutively active form of TGR5 (TGR5-Tg) display a better glucose tolerance, whereas high-fat-fed TGR5 KO mice have a worsened glycaemic profile. These improvements in glucose metabolism are due to the GLP-1-mediated incretin effect. Indeed, high-fat diet fed TGR5-Tg mice display more GLP-1 and insulin after an oral glucose tolerance test than WT mice thus highlighting the importance of the TGR5/GLP-1 pathway in the improvement of glycaemia by bile acids.

Farnesoid X receptor. Different studies have revealed that, depending on the organ, FXR activation can be beneficial or deleterious for glucose control in obesity. In 2006, Zhang et al.( Reference Zhang, Lee and Barrera 76 ) demonstrated that overexpressing a constitutively active form of FXR in the liver of db/db mice improves glucose tolerance. Moreover, ob/ob mice also display an improved glucose tolerance after intra-peritoneal injection of GW4064 (IP, 30 mk/kg mouse, once daily for 10 d) and have a decrease in insulin secretion( Reference Cariou, van Harmelen and Duran-Sandoval 77 ). A recent study shows that GW4064 treated mice (50 mk/kg mouse, by IP, twice weekly for 6 weeks) gain less body weight when fed a high-fat diet than vehicle-treated mice. GW4064 treated mice also display a better glucose tolerance than vehicle-treated mice( Reference Ma, Huang and Yan 78 ). These studies demonstrate that hepatic FXR activation decreases gluconeogenic genes expression. Moreover FXR activation also leads to the induction by glucose of glycolysis gene expression by interfering with the ChREBP pathway( Reference Caron, Huaman Samanez and Dehondt 79 ). Altogether, these results show that activating hepatic FXR seems beneficial for glucose control. Conversely, mice fed with a high-fat diet mixed with GW4064 display a lower bile acid pool size with a decrease in TCA proportion. They are also more obese and hyperglycaemic than mice fed with the control diet or fed with a high-fat diet enriched with CA 0·1 % showing a deleterious impact of oral GW4064 administration( Reference Watanabe, Horai and Houten 80 ). The involvement of the GLP-1 pathway in this phenotype is unclear since no GLP-1 measurements were performed. However, T2D obese patients treated with TCA have increased GLP-1 and lower blood glucose( Reference Adrian, Gariballa and Parekh 73 ). Moreover, we have shown in mice that oral administration of GW4064 (by gavage, 30 mk/kg mouse, once daily for 5 d) decreases proglucagon gene expression and intestinal biopsies from mice treated following this protocol failed to secrete GLP-1 in response to glucose( Reference Trabelsi, Daoudi and Prawitt 51 ). It should be noted that GW4064, as well as fexaramine( Reference Fang, Suh and Reilly 81 ), are not well absorbed by the intestine. Thus, the decreased GLP-1 pathway after intestinal FXR activation can be involved in the deleterious effect of oral GW4064 on glucose metabolism. As indicated earlier, four different isoforms of FXR (FXRα1–4) have been identified (for review( Reference Schonewille, de Boer and Groen 82 )). Whereas the expression levels of FXRα1–2 and FXRα3–4 are similar in the liver, the intestine expresses higher levels of FXRα3–4 than FXRα1–2( Reference Zhang, Kast-Woelbern and Edwards 30 ). Differences in FXR isoform expression profiles may be involved in the differences between the beneficial effect of FXR activation in the liver and its harmful action in the intestine. Further studies are needed to fully address the importance of each FXR isoform, and especially in the intestine, in energy homeostasis.

The importance of FXR on glucose homeostasis reached a milestone thanks to the development of both whole-body and tissue-specific FXR KO animals. Indeed, many studies demonstrate that whole-body FXR KO mice are protected against diet-induced or genetically induced obesity. These mice also have an improved glucose tolerance( Reference van Dijk, Grefhorst and Oosterveer 83 Reference Parséus, Sommer and Sommer 87 ). Van Dijk et al.( Reference van Dijk, Grefhorst and Oosterveer 83 ) have demonstrated that whole-body FXR KO mice present a delay in intestinal glucose absorption due to enterocytic accumulation of glucose-6-phosphate. In the hyperphagic ob/ob mice FXR gene expression deficiency improves all metabolic parameters and in particular glucose metabolism through an enhancement of peripheral glucose disposal and an increased adipose tissue insulin sensitivity( Reference Prawitt, Abdelkarim and Stroeve 84 ). These improvements are not observed in ob/ob mice where FXR gene is specifically invalidated in the hepatocyte thus demonstrating that FXR in extra-hepatic tissues drives the beneficial effects of FXR gene expression deficiency on glucose homeostasis.

A recent study shows that mRNA levels of FXR and its target genes small heterodimer partner and FGF19, are increased in the ileum of obese v. lean human subjects( Reference Jiang, Xie and Lv 88 ). Moreover, the expression of these genes positively correlates with BMI. Furthermore, bile diversion to the ileum in obese mice inhibits the expression of these genes and improves glucose metabolism( Reference Flynn, Albaugh and Cai 69 ). Jiang et al.( Reference Jiang, Xie and Lv 88 ) further demonstrate that administration of a bile acid with specific intestinal FXR antagonism improves metabolic parameters, such as triglyceridaemia and glucose clearance, in obese mice. These improvements are due to a decrease in intestinal ceramide production. Moreover, and according to the phenotype observed in whole-body FXR KO mice, intestinal specific FXR KO mice are protected against diet-induced obesity also through a reduction of intestinal ceramide production( Reference Jiang, Xie and Lv 88 , Reference Li, Jiang and Krausz 89 ). Finally, whereas FXR KO mice fed a high-fat diet have a reduced glycaemia after an oral glucose tolerance test. This improvement is lost after GLP-1R antagonism showing that the beneficial effect of FXR gene invalidation on glycaemia is in part mediated through a GLP-1/GLP-1R pathway( Reference Trabelsi, Daoudi and Prawitt 51 ). Altogether, these results highlight a role of intestinal FXR in glucose metabolism in a pathophysiological context of obesity and T2D.

Direct and indirect inhibitions of intestinal farnesoid X receptor by pharmacological agents as possible treatments for type 2 diabetes

Some recent studies suggest that intestinal FXR inhibition in a pathophysiological context of obesity improves glucose homeostasis. Here we will focus only on bile acid sequestrants and microbiota manipulation as two possible treatments for T2D via an inhibition of intestinal FXR.

Inactivation of intestinal farnesoid X receptor transcriptional activity using bile acid sequestrants

Bile acid sequestrants (BAS) are anionic exchange resins first used to decrease hypercholesterolaemia. Indeed, BAS increase HDL-cholesterol levels by 3–5 % and decrease by 15–30 % LDL-cholesterol without changing or slightly increasing TAG levels( Reference Brufau, Stellaard and Prado 64 , Reference Herrema, Meissner and van Dijk 90 ). By trapping bile acids in the intestinal lumen, these molecules increase their faecal output. Thus, bile acids cannot activate intestinal FXR leading to the inhibition of the negative feedback loop driven by FGF15/19. Hepatocytes continue to convert cholesterol into bile acids thus decreasing plasma cholesterol( Reference Brufau, Stellaard and Prado 64 , Reference Herrema, Meissner and van Dijk 90 ). In the USA, BAS are also used as antidiabetic drugs. Indeed, cholestyramine administration for 5 d to diabetic patients decreases glycaemia by 20 mg/dl and glucosuria by 40 g compared with placebo treated patients( Reference Garg and Grundy 91 , Reference Staels and Kuipers 92 ). The mechanisms behind such improvements are multiple and not fully identified. Among them, an increase in splanchnic glucose utilisation and an increase in GLP-1 secretion can participate in the improvements (for review( Reference Prawitt, Caron and Staels 93 )). Splanchnic glucose utilisation is defined by the hepatic absorption of portal glucose, coming from the intestine, and its metabolisation through glycogenesis or glycolysis. As mentioned earlier, FXR KO mice have a delay in intestinal glucose absorption( Reference van Dijk, Grefhorst and Oosterveer 83 ). Moreover, ob/ob FXR KO mice have an improved glucose homeostasis due to an improved glucose clearance and increased insulin sensitivity in adipose tissue. Colesevelam improves glucose homeostasis only in ob/ob FXR WT but not in FXR KO ob/ob mice showing that the beneficial effect of colesevelam is dependent on FXR( Reference Prawitt, Abdelkarim and Stroeve 84 ). Finally, hepatic FXR activation inhibits glucose-induced glycolytic gene expression( Reference Caron, Huaman Samanez and Dehondt 79 ). BAS, through lifting these repressions, increases hepatic glucose utilisation. These results are in accordance with the fact that BAS administered to T2D patients increase glucose clearance and insulin sensitivity. This study also demonstrated an increase in incretin secretion after colesevelam( Reference Beysen, Murphy and Deines 94 ).

BAS-stimulated GLP-1 secretion has been proposed to occur by inhibiting bile acid ileal reabsorption. Thus, BAS drive bile acids to the colon where L-cell density is the highest. More precisely, the bile acid in complexes with BAS are still able to bind and to activate L-cell-TGR5, thus increasing GLP-1 secretion( Reference Harach, Pols and Nomura 18 ). Potthoff et al.( Reference Potthoff, Potts and He 56 ) further demonstrated that the improvement of glycaemia after BAS is driven through a TGR5/GLP-1-induced reduction in hepatic glycogenolysis. Using colesevelam, Shang et al.( Reference Shang, Saumoy and Holst 95 ) have shown in Zucker diabetic fatty rats a decrease in glucose clearance together with an increase in GLP-1 secretion. As indicated earlier, BAS de-activate intestinal FXR activity by inhibiting bile acid flux through enterocytes. Together with an enhanced glucose clearance and a decrease in intestinal small heterodimer partner gene expression, Zucker diabetic fatty rats treated with BAS have an increased glucose-induced GLP-1 secretion( Reference Chen, McNulty and Anderson 96 ). We have shown that colesevelam treatment of ob/ob mice improves glucose clearance after an oral glucose tolerance test and increases GLP-1 production through FXR, because such improvements are not observed in ob/ob FXR KO mice( Reference Trabelsi, Daoudi and Prawitt 51 ) (Fig. 2).

Inactivation of intestinal farnesoid X receptor via microbiota manipulation

In recent years, a clear role of the gut microbiota in energy homeostasis regulation has emerged. Mice without intestinal microbiota (germ-free (GF) mice) are protected against diet-induced obesity and have an improved glycaemia compared with conventionally raised mice fed the same diet( Reference Bäckhed, Manchester and Semenkovich 97 ). Moreover, these GF mice have profound changes in bile acid metabolism. Indeed, GF mice have higher levels of  tauro-alpha MCA and tauro-beta MCA, two bile acids with FXR antagonist properties( Reference Sayin, Wahlström and Felin 32 ). Proglucagon mRNA levels and GLP-1 positive cells are also increased in GF mice compared with conventionally-raised mice( Reference Wichmann, Allahyar and Greiner 98 ). To link these two observations, we measured ileal proglucagon mRNA in both GF and conventionally raised FXR WT and FXR KO mice. FXR KO mice have increased proglucagon mRNA levels only in conventionally raised mice showing that the impact of FXR gene deficiency on proglucagon gene expression needs gut microbiota( Reference Trabelsi, Daoudi and Prawitt 51 ). Recent observations show that FXR WT and FXR KO mice have different gut microbiota( Reference Parséus, Sommer and Sommer 87 ). Moreover, high-fat fed GF mice transplanted with intestinal microbiota from FXR KO obese mice gain less body weight and display a better glucose tolerance than high-fat diet fed GF mice colonised with intestinal microbiota from FXR WT obese mice( Reference Parséus, Sommer and Sommer 87 ). Therefore, the beneficial effect of FXR gene deficiency on glucose tolerance involves the GLP-1 pathway and gut microbiota. Finally, treatment of obese mice with the prebiotic tempol enhances glucose metabolism through increased levels in bile acids with FXR antagonist properties. These improvements due to tempol treatment are not observed in intestinal FXR KO mice( Reference Li, Jiang and Krausz 89 ) and are in line with a study showing that feeding mice with the FXR antagonist GβMCA improves glucose tolerance through intestinal FXR( Reference Jiang, Xie and Lv 88 ). Thus, prebiotics which increase the levels of bile acids with FXR antagonist properties improve glucose metabolism.

Conclusion

Although some discrepancies remain on the overall role of the bile acid receptors TGR5 and FXR in glucose metabolism, recent studies clearly highlight that these receptors in the intestine seems to be crucial to maintain glucose homeostasis. To summarise, the intestinal bile acid receptors FXR and TGR5 appear valuable targets to treat diabetics. Whereas FXR activation in hepatocytes seems to be beneficial for improving glucose metabolism, its inhibition in intestine seems beneficial to improve glucose clearance and insulin sensitivity. TGR5 activation in L-cells increases the release of the incretin GLP-1 whereas in these cells FXR decreases the glucose-induced GLP-1 secretion. Moreover, in a pathophysiological context of obesity, whole-body, but also intestine-specific FXR gene expression deficiency ameliorates glucose homeostasis. These improvements are not observed in mice with an invalidation of FXR gene specifically in the hepatocyte. Finally, both BAS and the prebiotic tempol improve glucose homeostasis by inhibiting intestinal FXR thus highlighting valuable pharmacological tools to study the interplay between bile acids/FXR/GLP-1 in a pathophysiological context of obesity and T2D. Further studies are needed to fully address to which extend intestinal FXR inhibition is a good option to treat T2D patients.

Acknowledgements

We want to thank the French Society of Nutrition (Société Française de Nutrion) for providing the opportunity to Mohamed-Sami Trabelsi to attend the International Nutrition Student Research Championship symposium at the Nutrition Society Summer Conference: New Technology in Nutrition Research and Practice in Dublin. Bart Staels is a member of the Institut Universitaire de France.

Financial Support

M. S. T. was supported by a grant from the National Agency for Research (ANR# SVSE 1–2012 project SENSOFAT2).

Conflicts of Interest

None.

Authorship

M. S. T., S. L., B. S. and  X. C. drafted the manuscript; S. L., B. S. and X. C. revised the manuscript for important intellectual content; and X. C. obtained funding.

References

1. Pandak, WM, Bohdan, P, Franklund, C et al. (2001) Expression of sterol 12alpha-hydroxylase alters bile acid pool composition in primary rat hepatocytes and in vivo . Gastroenterology 120, 18011809.Google Scholar
2. Li-Hawkins, J, Gåfvels, M, Olin, M et al. (2002) Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J Clin Invest 110, 11911200.Google Scholar
3. Schwarz, M, Russell, DW, Dietschy, JM et al. (2001) Alternate pathways of bile acid synthesis in the cholesterol 7 alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding. J Lipid Res 42, 15941603.CrossRefGoogle ScholarPubMed
4. Luchoomun, J & Hussain, MM (1999) Assembly and secretion of chylomicrons by differentiated Caco-2 cells. Nascent triglycerides and preformed phospholipids are preferentially used for lipoprotein assembly. J Biol Chem 274, 1956519572.CrossRefGoogle ScholarPubMed
5. Hagenbuch, B & Meier, PJ (2004) Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflüg Arch 447, 653665.Google Scholar
6. Mazuy, C, Helleboid, A, Staels, B et al. (2015) Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci 72, 16311650.Google Scholar
7. Prawitt, J, Caron, S & Staels, B (2011) Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr Diab Rep 11, 160166.Google Scholar
8. de Aguiar Vallim, TQ, Tarling, EJ & Edwards, PA (2013) Pleiotropic roles of bile acids in metabolism. Cell Metab 17, 657669.Google Scholar
9. Dey, N, Wagner, VE, Blanton, LV et al. (2015) Regulators of gut motility revealed by a gnotobiotic model of diet-microbiome interactions related to travel. Cell 163, 95107.CrossRefGoogle ScholarPubMed
10. Rolo, AP, Palmeira, CM, Holy, JM et al. (2004) Role of mitochondrial dysfunction in combined bile acid-induced cytotoxicity: the switch between apoptosis and necrosis. Toxicol Sci 79, 196204.CrossRefGoogle ScholarPubMed
11. Morgan, WA, Nk, T & Ding, Y (2008) The use of high performance thin-layer chromatography to determine the role of membrane lipid composition in bile salt-induced kidney cell damage. J Pharmacol Toxicol Methods 57, 7073.Google Scholar
12. Perez, M-J & Briz, O (2009) Bile-acid-induced cell injury and protection. World J Gastroenterol 15, 16771689.Google Scholar
13. Prawitt, J & Staels, B (2010) Bile acid sequestrants: glucose-lowering mechanisms. Metab Syndr Relat Disord 8, Suppl. 1, S3S8.Google Scholar
14. Kawamata, Y, Fujii, R, Hosoya, M et al. (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278, 94359440.CrossRefGoogle Scholar
15. Maruyama, T, Tanaka, K, Suzuki, J et al. (2006) Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol 191, 197205.Google Scholar
16. Watanabe, M, Houten, SM, Mataki, C et al. (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484489.Google Scholar
17. Briere, DA, Ruan, X, Cheng, CC et al. (2015) novel small molecule agonist of tgr5 possesses anti-diabetic effects but causes gallbladder filling in mice. PLoS ONE 10, e0136873.CrossRefGoogle ScholarPubMed
18. Harach, T, Pols, TWH, Nomura, M et al. (2012) TGR5 potentiates GLP-1 secretion in response to anionic exchange resins. Sci Rep 2, 430.Google Scholar
19. Li, T, Holmstrom, SR, Kir, S et al. (2011) The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 25, 10661071.Google Scholar
20. Donepudi, AC, Boehme, S, Li, F et al. (2016) G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology. [Epublication ahead of print version]Google Scholar
21. Lou, G, Ma, X, Fu, X et al. (2014) GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. PLoS ONE 9, e93567.CrossRefGoogle ScholarPubMed
22. Alemi, F, Poole, DP, Chiu, J et al. (2013) The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 144, 145154.Google Scholar
23. Kidd, M, Modlin, IM, Gustafsson, BI et al. (2008) Luminal regulation of normal and neoplastic human EC cell serotonin release is mediated by bile salts, amines, tastants, and olfactants. Am J Physiol Gastrointest Liver Physiol 295, G260G272.Google Scholar
24. Grider, JR (2003) Neurotransmitters mediating the intestinal peristaltic reflex in the mouse. J Pharmacol Exp Ther 307, 460467.CrossRefGoogle ScholarPubMed
25. Grider, JR, Piland, BE, Gulick, MA et al. (2006) Brain-derived neurotrophic factor augments peristalsis by augmenting 5-HT and calcitonin gene-related peptide release. Gastroenterology 130, 771780.Google Scholar
26. Seol, W, Choi, HS & Moore, DD (1995) Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9, 7285.Google Scholar
27. Forman, BM, Goode, E, Chen, J et al. (1995) Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81, 687693.Google Scholar
28. Wang, H, Chen, J, Hollister, K et al. (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3, 543553.CrossRefGoogle ScholarPubMed
29. Mangelsdorf, DJ, Thummel, C, Beato, M et al. (1995) The nuclear receptor superfamily: the second decade. Cell 83, 835939.Google Scholar
30. Zhang, Y, Kast-Woelbern, HR & Edwards, PA (2003) Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 278, 104110.Google Scholar
31. Hu, X, Bonde, Y, Eggertsen, G et al. (2014) Muricholic bile acids are potent regulators of bile acid synthesis via a positive feedback mechanism. J Intern Med 275, 2738.CrossRefGoogle Scholar
32. Sayin, SI, Wahlström, A, Felin, J et al. (2013) Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17, 225235.Google Scholar
33. Campana, G, Pasini, P, Roda, A et al. (2005) Regulation of ileal bile acid-binding protein expression in Caco-2 cells by ursodeoxycholic acid: role of the farnesoid X receptor. Biochem Pharmacol 69, 17551763.Google Scholar
34. Sinal, CJ, Tohkin, M, Miyata, M et al. (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731744.CrossRefGoogle ScholarPubMed
35. Lu, TT, Makishima, M, Repa, JJ et al. (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6, 507515.CrossRefGoogle ScholarPubMed
36. Sanyal, S, Båvner, A, Haroniti, A et al. (2007) Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis. Proc Natl Acad Sci USA 104, 1566515770.Google Scholar
37. Lefebvre, P, Cariou, B, Lien, F et al. (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89, 147191.CrossRefGoogle ScholarPubMed
38. Chen, F, Ma, L, Dawson, PA et al. (2003) Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter. J Biol Chem 278, 1990919916.Google Scholar
39. Hwang, ST, Urizar, NL, Moore, DD et al. (2002) Bile acids regulate the ontogenic expression of ileal bile acid binding protein in the rat via the farnesoid X receptor. Gastroenterology 122, 14831492.Google Scholar
40. Boyer, JL, Trauner, M, Mennone, A et al. (2006) Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol 290, G1124G1130.Google Scholar
41. Lee, H, Zhang, Y, Lee, FY et al. (2006) FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. J Lipid Res 47, 201214.Google Scholar
42. Markan, KR & Potthoff, MJ (2016) Metabolic fibroblast growth factors (FGFs): mediators of energy homeostasis. Semin Cell Dev Biol 53, 8593.CrossRefGoogle ScholarPubMed
43. Owen, BM, Mangelsdorf, DJ & Kliewer, SA (2015) Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol Metab 26, 2229.CrossRefGoogle ScholarPubMed
44. Baggio, LL & Drucker, DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 21312157.CrossRefGoogle ScholarPubMed
45. Ward, C (2016) Metabolism, insulin and other hormones – Diapedia (Internet). Available from http://www.diapedia.org/5105252812/rev/7 (accessed August 2016).CrossRefGoogle Scholar
46. Parker, HE, Adriaenssens, A, Rogers, G et al. (2012) Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion. Diabetologia 55, 24452455.Google Scholar
47. Reimann, F, Habib, AM, Tolhurst, G et al. (2008) Glucose sensing in L cells: a primary cell study. Cell Metab 8, 532539.Google Scholar
48. Gorboulev, V, Schürmann, A, Vallon, V et al. (2012) Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61, 187196.Google Scholar
49. Kuhre, RE, Frost, CR, Svendsen, B et al. (2015) Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine. Diabetes 64, 370382.CrossRefGoogle ScholarPubMed
50. Daoudi, M, Hennuyer, N, Borland, MG et al. (2011) PPARβ/δ activation induces enteroendocrine L cell GLP-1 production. Gastroenterology 140, 15641574.Google Scholar
51. Trabelsi, M-S, Daoudi, M, Prawitt, J et al. (2015) Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun 6, 7629.CrossRefGoogle ScholarPubMed
52. Habib, AM, Richards, P, Cairns, LS et al. (2012) Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153, 30543065.Google Scholar
53. Filhoulaud, G, Guilmeau, S, Dentin, R et al. (2013) Novel insights into ChREBP regulation and function. Trends Endocrinol Metab 24, 257268.Google Scholar
54. Vallim, TQ & Edwards, PA (2009) Bile acids have the gall to function as hormones. Cell Metab 10, 162164.Google Scholar
55. Thomas, C, Gioiello, A, Noriega, L et al. (2009) TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10, 167177.Google Scholar
56. Potthoff, MJ, Potts, A, He, T et al. (2013) Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol 304, G371G380.Google Scholar
57. Bala, V, Rajagopal, S, Kumar, DP et al. (2014) Release of GLP-1 and PYY in response to the activation of G protein-coupled bile acid receptor TGR5 is mediated by Epac/PLC-ε pathway and modulated by endogenous H2S. Front Physiol 5, 420.CrossRefGoogle Scholar
58. Brighton, CA, Rievaj, J, Kuhre, RE et al. (2015) Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 156, 39613970.CrossRefGoogle ScholarPubMed
59.World Health Organization (2016) Obesity and Overweight: Fact Sheet. http://www.who.int/mediacentre/factsheets/fs311/en/ (accessed September 2016).Google Scholar
60.World Health Organization (2016) Diabetes: Fact sheet http://www.who.int/mediacentre/factsheets/fs312/en/ (accessed September 2016).Google Scholar
61. Huang, PL (2009) A comprehensive definition for metabolic syndrome. Dis Model Mech 2, 231237.Google Scholar
62. Bennion, LJ & Grundy, SM (1977) Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med 296, 13651371.Google Scholar
63. Abrams, JJ, Ginsberg, H & Grundy, SM (1982) Metabolism of cholesterol and plasma triglycerides in nonketotic diabetes mellitus. Diabetes 31, 903910.Google Scholar
64. Brufau, G, Stellaard, F, Prado, K et al. (2010) Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology 52, 14551464.Google Scholar
65. Suhre, K, Meisinger, C, Döring, A et al. (2010) Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting. PLoS ONE 5, e13953.Google Scholar
66. Sonne, DP, van Nierop, FS, Kulik, W et al. (2016) Postprandial plasma concentrations of individual bile acids and FGF-19 in patients with type 2 diabetes. J Clin Endocrinol Metab 101, 30023009.Google Scholar
67. Haeusler, RA, Astiarraga, B, Camastra, S et al. (2013) Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids. Diabetes 62, 41844191.Google Scholar
68. Goncalves, D, Barataud, A, De Vadder, F et al. (2015) Bile routing modification reproduces key features of gastric bypass in rat. Ann Surg 262, 10061015.Google Scholar
69. Flynn, CR, Albaugh, VL, Cai, S et al. (2015) Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery. Nat Commun 6, 7715.CrossRefGoogle Scholar
70. Pierre, JF, Martinez, KB, Ye, H et al. (2016) Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice. Am J Physiol Gastrointest Liver Physiol 311, G286G304.Google Scholar
71. Kohli, R, Kirby, M, Setchell, KDR et al. (2010) Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities. Am J Physiol Gastrointest Liver Physiol 299, G652G660.Google Scholar
72. Wu, T, Bound, MJ, Standfield, SD et al. (2013) Effects of rectal administration of taurocholic acid on glucagon-like peptide-1 and peptide YY secretion in healthy humans. Diab Obes Metab 15, 474477.Google Scholar
73. Adrian, TE, Gariballa, S, Parekh, KA et al. (2012) Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers. Diabetologia 55, 23432347.Google Scholar
74. Bianco, AC, Maia, AL, da Silva, WS et al. (2005) Adaptive activation of thyroid hormone and energy expenditure. Biosci Rep 25, 191208.Google Scholar
75. Vassileva, G, Hu, W, Hoos, L et al. (2010) Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice. J Endocrinol 205, 225232.Google Scholar
76. Zhang, Y, Lee, FY, Barrera, G et al. (2006) Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA 103, 10061111.Google Scholar
77. Cariou, B, van Harmelen, K, Duran-Sandoval, D et al. (2006) The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281, 1103911049.Google Scholar
78. Ma, Y, Huang, Y, Yan, L et al. (2013) Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res 30, 14471457.Google Scholar
79. Caron, S, Huaman Samanez, C, Dehondt, H et al. (2013) Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes. Mol Cell Biol 33, 22022211.Google Scholar
80. Watanabe, M, Horai, Y, Houten, SM et al. (2011) Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem 286, 2691326920.Google Scholar
81. Fang, S, Suh, JM, Reilly, SM et al. (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21, 159165.Google Scholar
82. Schonewille, M, de Boer, JF & Groen, AK (2016) Bile salts in control of lipid metabolism. Curr Opin Lipidol 27, 295301.CrossRefGoogle ScholarPubMed
83. van Dijk, TH, Grefhorst, A, Oosterveer, MH et al. (2009) An increased flux through the glucose 6-phosphate pool in enterocytes delays glucose absorption in Fxr−/− mice. J Biol Chem 284, 1031510323.Google Scholar
84. Prawitt, J, Abdelkarim, M, Stroeve, JHM et al. (2011) Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 60, 18611871.Google Scholar
85. Bjursell, M, Wedin, M, Admyre, T et al. (2013) Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH. PLoS ONE 8, e64721.Google Scholar
86. Ryan, KK, Tremaroli, V, Clemmensen, C et al. (2014) FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183188.Google Scholar
87. Parséus, A, Sommer, N, Sommer, F et al. (2016) Microbiota-induced obesity requires farnesoid X receptor. Gut [Epublication ahead of print version].Google ScholarPubMed
88. Jiang, C, Xie, C, Lv, Y et al. (2015) Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 6, 10166.Google Scholar
89. Li, F, Jiang, C, Krausz, KW et al. (2013) Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 4, 2384.Google Scholar
90. Herrema, H, Meissner, M, van Dijk, TH et al. (2010) Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor- and liver X receptor alpha-controlled metabolic pathways in mice. Hepatology 51, 806816.Google Scholar
91. Garg, A & Grundy, SM (1994) Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial. Ann Intern Med 121, 416422.CrossRefGoogle ScholarPubMed
92. Staels, B & Kuipers, F (2007) Bile acid sequestrants and the treatment of type 2 diabetes mellitus. Drugs 67, 13831392.Google Scholar
93. Prawitt, J, Caron, S & Staels, B (2014) Glucose-lowering effects of intestinal bile acid sequestration through enhancement of splanchnic glucose utilization. Trends Endocrinol Metab 25, 235244.Google Scholar
94. Beysen, C, Murphy, EJ, Deines, K et al. (2012) Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia 55, 432442.Google Scholar
95. Shang, Q, Saumoy, M, Holst, JJ et al. (2010) Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1. Am J Physiol Gastrointest Liver Physiol 298, G419G424.Google Scholar
96. Chen, L, McNulty, J, Anderson, D et al. (2010) Cholestyramine reverses hyperglycemia and enhances glucose-stimulated glucagon-like peptide 1 release in Zucker diabetic fatty rats. J Pharmacol Exp Ther 334, 164170.Google Scholar
97. Bäckhed, F, Manchester, JK, Semenkovich, CF et al. (2007) Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 104, 979984.CrossRefGoogle ScholarPubMed
98. Wichmann, A, Allahyar, A, Greiner, TU et al. (2013) Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 14, 582590.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1. (Colour online) Enterohepatic cycle of bile acids. Bile acids are produced from cholesterol in the liver. In the fasted state, bile acids are stored in the gallbladder. After meal ingestion, bile acids are expulsed in the intestinal lumen where they emulsify dietary fat. In the ileum, 95 % of bile acids are reabsorbed by the apical sodium-dependent bile salt transporter (ASBT) and basolateral heterodimer organic solute transporter α/β (OSTα/OSTβ). Through the portal circulation, bile acids return to the liver where, by their binding to FXR, they decrease gene expression of the rate-limiting enzymes in bile acid synthesis, i.e. Cyp7a1 and Cyp8b1. In enterocytes, the activated farnesoid X receptor (FXR) increases Fgf15/19 and Shp gene expression thus participating to bile acid metabolism regulation. In L-cells, bile acids bind and activate G-protein-coupled bile acid receptor 1 (TGR5) leading to the secretion of the incretin glucagon-like peptide 1 (GLP-1). By contrast, the activated FXR in L-cells decreases glucose-induced GLP-1 secretion.

Figure 1

Fig. 2. (Colour online) Activation of bile acid receptors in L-cells modulates glucagon-like peptide-1 (GLP-1) production and secretion. Activation of L-cell G-protein-coupled bile acid receptor 1 (TGR5) increases intracellular cAMP levels, thus leading to an increase in both GLP-1 production and secretion through the protein kinase (PK) A/cAMP responsive elements binding protein pathway and exchange protein directly activated by cAMP (EPAC2)/diacylglycerol (DAG)/PKCζ and EPAC2/phospholipase C (PLCε)/insulinotropic polypeptide (IP)3 pathways, respectively. Activation of L-cell farnesoid X receptor (FXR) in the presence of glucose decreases the glycolysis pathway, thus leading to lower intracellular ATP levels. This decrease is associated with lower levels of GLP-1. Moreover, FXR is in the same complex as carbohydrate responsive element-binding protein (ChREBP) and decreases glucose-induced proglucagon gene expression. The bile acid sequestrant (BAS) colesevelam, by inhibiting FXR activation, prevents these decreases. Furthermore, bile acid in complexes with BAS are still able to activate TGR5, thus further increasing L-cell GLP-1 secretion.