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Abstract

Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here, the basic chemistry and regulation of bile acids as well as their metabolic effects will be reviewed. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined.

Keywords

Bile acids metabolic syndrome type 2 diabetes mellitus non-alcoholic fatty liver disease farnesoid X receptor Takeda G-protein coupled receptor 5

Introduction

There is a close two-way relationship between bile acid homeostasis and nutrition. The synthesis, secretion and cycling of bile acids are governed by timing and content of food ingestion, and bile acid signalling regulates the subsequent metabolism of available fuel. Interest in bile acid biology has increased in recent years, due to global public health crises of obesity and related metabolic disorders. The number of people with obesity worldwide is more than 650 million, according to a 2016 estimate by the World Health Organization,¹ and in the UK alone, there are six million people with type 2 diabetes (T2DM).² Other metabolic diseases that are directly related to the pandemic of obesity include hypercholesterolaemia and non-alcoholic fatty liver disease (NAFLD). NAFLD, which is widely considered the hepatic manifestation of the metabolic syndrome, has an estimated global prevalence of 25%³ and is strongly associated with both obesity and T2DM.³

Increased appreciation of bile acids as metabolic regulators has led to two major research questions. Firstly, how does bile acid homeostasis change in metabolic disease? Secondly, can bile acid activity be harnessed to treat metabolic disease? Both will be addressed in this review.

Bile acid chemistry

Bile acid structure

Bile salts, which include bile acids and bile alcohols, have a central sterol ring.⁴ Beyond this common feature, bile salts comprise a vast and varied family of small molecules. The bile of each species is comprised of multiple different salts, with tremendous diversity in the resulting bile salt profile among vertebrates.⁵ This diversity likely represents parallel evolution of multiple biochemical pathways all serving to convert cholesterol, a crucial cellular component, but a hydrophobic and poorly soluble lipid, into a water-soluble molecule.^4–6

Bile acids are planar amphipathic molecules with a carboxyl tail.⁷ On one surface they display a hydroxyl group and on the other they project hydrophobic methyl groups.⁸ The overall polarity and solubility depend on the bile acid species and its chemical structure. At low concentrations, bile acids dissolve in water, whereas at high concentrations, they self-associate to form aggregates, also known as micelles. This occurs because hydrophobic faces of multiple molecules line up to repel water, while the hydrophilic faces become oriented towards the surrounding water.⁸

Primary bile acid biosynthesis

In mammals, there are two major biosynthetic pathways to commence formation of bile acids: ‘classic’ or ‘neutral’, and ‘alternate’ or ‘acidic’.⁹ Synthesis of the majority of bile acids involves the classic pathway in which hydroxylation of the cholesterol steroid nucleus is performed by cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the pathway.^4,10 This enzyme is a member of the P450 enzyme family and is a liver-specific, microsomal mono-oxidase. Ninety per cent of mice that lack CYP7A1 die in the neonatal period, with severe malnourishment resulting from fat-soluble vitamin deficiencies and lipid malabsorption.^4,11 The survival curve of animals surviving until day 18, however, subsequently flattens out,¹¹ and the observation that such animals are able to synthesize normal bile acids, in reduced number but sufficient for normal cholesterol metabolism, led to the description of the ‘alternate pathway’.¹²

The alternate pathway uses oxysterols as starting substrates for bile acid synthesis rather than cholesterol, and primarily extra-hepatic. Sterol side chain oxidation is catalysed by a sterol hydroxylase (e.g. sterol 27 hydroxylase, CYP27A1), and then 7α hydroxylation is catalysed by 25-hydroxycholesterol 7α hydroxylase, CYP7B1.⁴ The latter is the rate-limiting step. In healthy humans, these pathways are likely to contribute little to overall bile acid production,¹³ but they play a particular role in cholesterol turnover in certain tissues including brain, vascular endothelium and lung.^13–16

Oxysterol intermediates resulting from either pathway then undergo further modification in the liver. In the presence of sterol 12α-hydroxylase (CYP8B1), the intermediate is converted to cholic acid; in its absence, it is converted to chenodeoxycholic acid (CDCA) (rats, humans and hamsters) or β-muricholic acid (rodents).⁴ Hepatic expression of CYP8B1 therefore regulates the ratio of cholic to CDCA, and the resulting hydrophobicity of the bile acid pool.^4,17

Bile acid classification

Bile acids may be classified into primary, secondary and tertiary. Those synthesized from cholesterol in hepatocytes, as described in the previous section, are termed primary.¹⁰

Primary bile acids are conjugated within hepatocytes before being secreted into bile.¹⁰ There are five recognized types of conjugation, which occur at different locations of the steroid nucleus and side chain: N-acyl amidation with glycine or taurine; sulfation; ester glucuronidation; ethereal conjugation and N-acetylglucosamination.⁶ The first of these, conjugation of the terminal side chain carboxylic acid with glycine or taurine, is performed by the enzyme bile acid CoA: amino acid N-acyltransferase (BAAT) and can be considered the final stage of bile acid synthesis, as it occurs to all newly synthesized bile acids in hepatocyte peroxisomes prior to excretion.⁷

Conjugation with taurine or glycine increases bile acid solubility, and results in a molecule which is negatively charged at the pH of digestive fluids (pH 6–7).⁶ Furthermore, the size of the conjugated molecule is too large to diffuse through paracellular junctions. Due to these factors, newly secreted conjugated bile acids are highly concentrated in the lumen of the small intestine, which is crucial to enable satisfactory digestion of lipids.¹⁸

When primary bile acids are modified by enzymes, they become secondary bile acids; such modifications include removal, oxidation or epimerization of the nuclear hydroxyl groups. For example, the anaerobic bacteria in the caecum remove the hydroxyl group at C7 of CDCA and cholic acid, to form lithocholic acid (LCA) and deoxycholic acid (DCA), respectively.⁶ Although some modifications are introduced by hepatic enzymes, gut bacteria play a major role in the metabolism of primary bile acids; indeed, germ-free rodents and those treated with antibiotics have far lower bile acid diversity than control animals.^19,20 Bile acids which are then further biotransformed in the liver, after reabsorption from the gut, are in some texts named ‘tertiary’.²¹

The complicated nomenclature of bile acids may be attributed to the fact that many were isolated long before their chemical structure was elucidated. For example, chenodeoxycholic acid was named after the species from which it was first isolated (‘chena’ means ‘goose’ in Greek), whereas deoxycholic acid was named for its differences to cholic acid, the first bile acid to be identified and assigned a chemical formula in the late 19th century.²² In humans, the vast majority of circulating bile acids comprise cholic, DCA and CDCAs, and their glycine- and taurine-conjugated forms.^23,24

Enterohepatic circulation of bile acids

There exists a highly efficient system for bile acid conservation and recycling within the body, which is termed the enterohepatic circulation. After synthesis in the liver, bile salts are secreted into bile ducts, from where they either enter the intestine or are stored in the gallbladder.⁶ Upon meal ingestion, cholecystokinin drives gallbladder contraction and emptying, causing secretion of bile via the bile ducts into the intestine, where emulsification of nutrients occurs.²⁵ The vast majority of secreted bile acids (95%) then travel in the portal circulation back to the liver.⁴ The remaining 5% is excreted in faeces and is replaced by newly synthesized bile acids in the liver from cholesterol. This cycle repeats 4 to 10 times daily.²⁶

Bile acid transport

As they move within the enterohepatic circulation, conjugated bile acids undergo active transportation from one compartment to another (reviewed by Zwicker and Agellon¹⁰). The genes that express bile acid transporters are often regulated by bile acids themselves. This system allows for precise and responsive distribution of bile acids in accordance with meal status.

Major players in this process include the apical sodium-dependent bile acid transporter, expressed on the luminal side of ileal enterocytes, which is responsible for the uptake of luminal bile acids from the small bowel,²⁷ and the heterotrimeric organic solute transporter (OSTα/β) expressed on the basolateral membrane of the enterocytes, which secretes bile acids into the portal bloodstream.²⁸ In the liver, the sodium/taurocholate co-transporting polypeptide (NTCP) uptakes bile acids into hepatocytes.²⁹ These recycled bile acids, along with newly synthesized bile acids, are secreted into bile from the canalicular membrane of the hepatocytes via the bile salt export pump (BSEP or ABCB11).

Metabolic actions of bile acids (Table 1)

Bile acids have direct emulsification and solubilization properties on luminal lipids. Additionally, they act as signalling molecules on various receptors, with multiple downstream effects on metabolism. The best studied of these are the nuclear farnesoid X receptor (FXR) and the G-protein coupled membrane receptor Takeda G-protein-receptor-5 (TGR5), as detailed in this section.

Table 1.

Major metabolic actions of bile acids (see text for details).

Disease^a	Relevant bile acid action	Location	Receptor
Fat-soluble vitamin malabsorption (A,D,E,K)	Emulsification and solubilization of fat	Intestinal lumen	Direct effect
Hyperlipidaemia/coronary artery disease	Cholesterol elimination	Intestinal lumen	Direct effect

T2DM	Decrease gluconeogenesis	Hepatocytes	FXR
NAFLD	Decrease lipid deposition and inflammation
Hyperlipidaemia	Increase triglyceride clearance
MS	Decrease FGF19 production, leading to increased EE	Enterocytes
T2DM	Increase glucose-stimulated insulin secretion	Pancreatic α cells

MS	Increase secretion of GLP1 and PYY	Enterocytes	TGR5
MS	Increase energy expenditure	Brown adipose tissue/myocytes
MS	Anti-inflammatory	Immune cells

MS	Decrease ER stress	Multiple	GRP78

FXR: farnesoid X receptor; T2DM: type 2 diabetes; NAFLD: non-alcoholic fatty liver disease; FGF19: fibroblast growth factor 19; GLP-1: glucagon-like peptide 1; PYY: peptide tyrosine tyrosine; ER: endoplasmic reticulum; GRP78: glucose regulating protein 78; EE: energy expenditure; MS: metabolic syndrome (i.e. obesity and all related conditions).

^aMetabolic disease for which this effect is most relevant.

Individual bile acids differ in their ability to bind to and stimulate different receptors. The great diversity of circulating bile acids, which are engaged in a dynamic process of synthesis, cycling and modification in response to environmental factors such as dietary intake, allows for tight modulation of bile acid-stimulated responses.⁴

Lipid digestion and absorption

Bile acids emulsify dietary fats, converting them from fat globules into tiny droplets. The resulting increase in surface area renders the fats amenable to digestion by pancreatic enzymes. An example is bile salt-dependent lipase, which catalyses the hydrolysis of cholesterol esters into free cholesterol and fatty acids, enabling their absorption by the intestinal mucosa.³⁰ Bile acids also solubilize lipids by incorporating them into micelles. Certain essential vitamins (A, D, E and K) are non-polar lipids and require incorporation into micelles in order to be absorbed.^31,32 In most animals and healthy humans, both the production of bile acids and their elimination are modulated in response to varying dietary intake of cholesterol.^33,34 Diminished bile acid excretion predicts presence and severity of coronary artery disease.^34,35 In this way, bile acid circulation plays a key role in physiological cholesterol homeostasis.³⁶

Actions of bile acids mediated by FXR

FXR is a nuclear transcription factor, which forms a complex with retinoic X receptor and then binds to gene promoter regions.³⁷ FXR is highly expressed in human liver and gut, as well as in kidney, adrenals, vascular smooth muscle, white adipose tissue and immune cells.³⁸ Various biological features regulate and integrate the activity of FXR with other stimuli. Firstly, there are four isoforms of FXR, which are differentially expressed in different tissues.³⁹ The isoforms vary in their responsiveness to bile acid stimulation, with the isoform most commonly expressed in liver (FXRα1) exhibiting the greatest responsiveness in vitro.⁴⁰ Secondly, as a typical eukaryote nuclear transcription factor, activation of FXR releases corepressor complexes and/or stabilizes coactivator complexes in the promoter region of target genes. Multiple cofactors interact with FXR, and their recruitment is often also ligand dependent.³⁸

FXR is critical to the homeostatic-negative feedback cycle, which regulates bile acid synthesis and distribution; and additionally, it has key beneficial metabolic effects on multiple systems.

In hepatocytes, FXR activation increases small heterodimer partner (SHP) expression, which represses CYP7A1 expression, thereby reducing synthesis of bile acids via the classic pathway.⁴¹ SHP also represses NTCP, which decreases uptake of bile acids by the liver from the portal circulation.⁴² FXR increases bile acid efflux from the liver into bile by increasing BSEP expression⁴³ and also into the portal circulation by upregulating OSTα/β.⁴⁴ In these ways, hepatocyte FXR detects intracellular bile acids and activates mechanisms to decrease their excessive and potentially toxic accumulation.

Additionally, the activation of SHP suppresses CYP8B1 activity, which decreases the ratio of cholic acid to CDCA. A relative decrease in cholate to other bile acids increases the hydrophilicity of the circulating bile acid pool, thereby decreasing intestinal cholesterol absorption.^4,45 Cholic acid itself is a negative regulator of CYP7A1, and reduction in circulating cholic acid increases CYP7A1 activation.⁴⁶ Thus, a negative feedback loop maintains bile acid production in this complex system.

In human enterocytes, FXR activation increases production and secretion of fibroblast growth factor 19 (FGF19; or its orthologue FGF15, in mice). This circulates in portal blood and activates the hepatic fibroblast growth factor receptor 4 (FGFR4). Activation of FGFR4 also powerfully represses CYP7A1. Although FGF19 is also released from hepatocytes on FXR activation,⁴⁷ the intestinal route is likely to be the dominant effector of CYP7A1 repression.⁴⁸ In obese rodents, FGF19 has been shown to act centrally to increase energy expenditure, decrease weight and improve glucose tolerance.⁴⁹

FXR increases hepatic triglyceride clearance, by modifying the expression of several genes involved in lipid transport and metabolism. For example, it reduces the expression of apolipoprotein CIII⁵⁰ and increases the expression of apolipoprotein CII,⁵¹ apolipoprotein E⁵² and phospholipid transfer protein.⁵³ Furthermore, FXR increases hepatic uptake of low-density lipoprotein (LDL) and very low density lipoprotein (VLDL) by increasing hepatocyte expression of syndecan-1, a transmembrane proteoglycan that participates in LDL binding and internalization, and VLDL-receptor.^54,55 Accordingly, FXR(–/–) mice have increased plasma cholesterol and triglycerides.⁵⁶

Deletion of FXR increases susceptibility to hepatic steatosis in mice.^57,58 FXR activation may be directly protective for NAFLD, by decreasing hepatic lipid deposition and activating anti-inflammatory pathways.⁵⁹ Patients with non-alcoholic steatohepatitis (NASH) have lower hepatic protein expression of FXR and SHP compared to those with simple steatosis.⁶⁰ Key nuclear transcription factors involved in hepatic lipid metabolism include sterol regulatory element-binding protein 1c, which promotes lipogenesis and is repressed by FXR, and peroxisome proliferator-activated receptor α, which increases fatty acid oxidation and is increased by FXR.⁶¹ A major mechanism through which FXR decreases inflammation in the liver is through nuclear factor κβ, a process which can be reversed by aberrant acetylation of FXR.⁶²

Hepatic FXR also governs hepatic gluconeogenesis. Via SHP, it suppresses key enzymes involved in this pathway, including phosphoenol-pyruvate carboxykinase and glucose 6-phosphatase (G6Pase).⁵⁸ In adipocytes, both FXR agonism and stimulation with FGF19 cause increased glucose uptake.^63,64 Furthermore, in pancreatic β cells, FXR agonism inhibits membrane potassium channels, which increases calcium influx, resulting in greater glucose-stimulated insulin secretion.^65,66

Actions mediated by TGR5

TGR5 is a bile acid receptor located on the cell membrane,⁶⁷ also known as the membrane-bile acid receptor or G protein bile acid-activated receptor.⁶⁸ Gene expression of this receptor is ubiquitous in human and rodent tissues, with higher levels in lung, liver, gallbladder, spleen, fat, central nervous system and gut.⁶⁸ Immunohistochemical analysis of mouse gastrointestinal tract has shown that TGR5 is found in the enteric nervous system, mainly in inhibitory neurons.⁶⁹ TGR5 is a proto-typical transmembrane G protein-coupled receptor, activation of which leads to intracellular signalling via adenylyl cyclase and cyclic AMP.⁶⁷ Depending on the cell line, TGR5 activation may also lead to increase or lowering of intracellular calcium levels.^70,71 In vitro, LCA, DCA and CDCA stimulate TGR5 robustly, whereas ursodeoxycholic acid (UDCA) does not.⁷²

Within the liver, TGR5 is abundant in non-hepatocytes, including cholangiocytes, gallbladder epithelial cells, Kupffer immune cells and liver sinusoidal epithelium. Stimulation of TGR5 in these biliary tree locations allows bile acids to act in a paracrine manner, streamlining biliary activity according to bile acid flux. For example, activation of TGR5 in vascular endothelial cells causes vasodilation, increasing hepatic blood flow.⁷³ TGR5 activation in gallbladder epithelium leads to chloride secretion into bile, probably via the cystic fibrosis transmembrane chloride channel.⁷⁴ TGR5 stimulation also relaxes the smooth muscle of the gallbladder wall, allowing it to fill with bile.⁷⁵

Bile acids have also been known for some time to stimulate enterocyte secretion of gut hormones involved in blood sugar and appetite regulation.⁷⁶ These include glucagon-like peptide 1, an incretin hormone which augments insulin secretion in response to oral glucose; and peptide YY, a centrally active anorectic hormone. Recent mechanistic studies demonstrate that these effects are likely to occur secondary to intestinal absorption of bile acids, primarily via stimulation of TGR5 on the basolateral membranes of enterocytes.^72,77

Another key beneficial metabolic effect of bile acids occurs via the TGR5 receptor in brown adipose tissue (BAT). In mice, bile acid activation of TGR5 in BAT increases energy expenditure, thereby providing resistance to obesity and improvements in metabolic health.⁷⁸ This occurs via activation of type 2 iodothyronine deiodinase, which converts inactive thyroxine into active 3,5,3′-triiodothyronine. Although adult humans have only small amounts of BAT, the same pathway has been shown to occur in vitro in human skeletal myocytes, provoking increased cellular energy expenditure.⁷⁸

Other biological effects of bile acids mediated through TGR5 include anti-inflammatory effects in monocytes and macrophages.^79,80 Stimulation of TGR5 inhibits production of pro-inflammatory cytokines. TGR5 mediates the stimulatory effects of bile acids on colonic peristalsis, and lack of this pathway results in constipation in mice.⁸¹ Additionally, TGR5 on sensory nerves mediates pruritus and analgesia,⁸² characteristic symptoms of patients with obstructing biliary disease and hence high circulating bile acids.⁸³

Reduction of endoplasmic stress

The endoplasmic reticulum (ER) is responsible for folding new proteins via chaperones and foldases. Where the ER’s capacity for protein folding is overwhelmed (for example, when there is excessive protein synthesis or abnormal proteins), misfolded proteins accumulate in the ER and cause ER stress.⁸⁴ In response, the unfolded protein response (UPR) is triggered. Initially, this is adaptive, preventing translation of further proteins and promoting autophagy of existing proteins, but if ER homeostasis is not regained, it ultimately leads to cell apoptosis.

ER stress is increased in obesity,⁸⁵ and it is heavily implicated in the pathogenesis of obesity and diseases of insulin resistance. In adipose tissues, ER stress induces inflammation and the secretion of harmful adipokines; in pancreatic tissues, ER stress can impair insulin synthesis.⁸⁶ Additionally, ER stress leads to phosphorylation of insulin receptor-substrate 1 and suppression of insulin receptor signalling in liver and adipose tissues.⁸⁷

Tauroursodeoxycholate (TUDCA) has been demonstrated in vitro to decrease ER stress in hepatoma cells, intestinal epithelial cells and cardiac myoblasts.^87,88 Cholic acid, a major endogenous bile acid, also reduces tunicamycin-induced ER stress in cultured hepatoma cells, adipocytes and pancreatic β-cells.⁸⁹ The mechanism is not fully understood but appears to involve the modulation of expression of a key ER chaperone glucose regulating protein, GRP78. GRP78 is increased via TUDCA-mediated phosphorylation of upstream molecules (PI3K/Akt and PKG) in cardiac cells⁸⁸ and decreased by UDCA in intestinal cells, in both cases reducing ER stress.

Changes in bile acid circulation in health and disease

Total and individual bile acid concentrations in different physiological compartments are highly variable with metabolic state. The chemical diversity of different bile acid species and their wide concentration ranges can make comprehensive analysis challenging. There is often a compromise between bile acid coverage and rate of throughput.⁹¹ Bile acids are most frequently analysed from plasma of peripheral blood, although they can be extracted from other biofluids, commonly faeces, luminal gut content and urine.⁹²

Circulating bile acid fluctuations in metabolic health

Postprandially, there is an increase in delivery of bile acids to the duodenum, from where they are efficiently returned via the portal circulation to hepatocytes. Postprandial concentrations of portal vein bile acids increase up to six-fold, peaking at 15–60 min after a meal.⁹³ Hepatocytes clear bile acids into bile canaliculi and systemic blood; the rate of the former remains relatively constant, while the spillover rate into circulating blood is adjusted according to the rate of delivery to hepatocytes.^93,94 There is a good correlation between portal and peripheral venous bile acid concentrations, with the former approximately six to seven times higher than the latter.⁹³ Fasting total serum bile acids are typically below 5 μM, and may rise as high as 10–15 μM postprandially.^23,94,95 Meals with a higher fat content stimulate a higher postprandial bile acid rise.²³ Peak circulating bile acids are seen at around 1 to 2 hours postprandially.^23,96

Hepatic fractional uptake varies between bile acid species, such that there is an enrichment of systemic glycine-conjugated primary bile acids postprandially.^23,96 A similar response is seen after ingestion of glucose alone, with a rise in conjugated bile acids from 30 min after oral glucose tolerance test (OGTT).^97–99

Fasting total plasma bile acid concentrations have been reported to be higher in men than women,¹⁰⁰ although a study of non-fasting samples found them to be non-significantly higher in women.²⁴ One study reported that concentrations of most individual fasting bile acids falls with age, although for several species of bile acids this was gender dependent¹⁰⁰; conversely, another group demonstrated no change with age.²⁴ There may also be ethnic differences in circulating bile acids, with a recent report of higher serum concentrations of glycocholic acid, glycochenodeoxycholic acid (GCDCA), CDCA and taurochenodeoxycholic acid in Asians compared with Caucasians.²⁴ The variation in study conclusions may well relate to unexplored biological variables as well as assay variability.

Fluctuations in bile acid synthesis

As outlined earlier, de novo synthesis of bile acids is regulated by negative feedback mechanisms; bile acid-stimulated secretion of FGF19 from enterocytes plays a particularly important role by suppressing hepatocyte CYP7A1. Administration of CDCA orally for two weeks increases circulating FGF19, decreases CYP7A1 activity and decreases endogenous bile acid synthesis.^101,102 Conversely, treatment with cholestyramine, a bile acid sequestrant which prevents intestinal bile acid resorption, leads to a decrease in circulating FGF19, increase in hepatic CYP7A1 activity and increased bile acid synthesis.^101,102

Bile acid synthesis has a diurnal pattern, with peaks occurring in the middle of the day and in the evening.¹⁰³ Rate of synthesis is higher in men than in women and positively correlated with plasma triglyceride level.²⁶ Bile acid synthesis decreases with age, and this is associated with an increase in plasma cholesterol.¹⁰⁴ An increased rate of bile acid synthesis is associated with the development of gallstone disease.¹⁰⁵ An increased rate has also been demonstrated in volunteers lacking a gallbladder.²⁶

Bile acid homeostasis in obesity and diseases of insulin resistance

To date, studies of bile acid pool size have involved small numbers of individuals, and results are often contradictory. Most agree that mildly insulin-resistant individuals tend towards higher total fasting circulating bile acids.^106–109 Some^23,107–109 but not all⁹⁵ studies reported higher fasting total bile acids in patients with T2DM. Similarly, there is controversy regarding the level of total bile acids in fasting obese patients: two studies reported comparable levels to normal weight controls,^96,110 while another reported higher total bile acids in obese patients.¹⁰⁶

In patients with obesity, the rise in circulating bile acids in response to a meal stimulus is suppressed.^96,110 Metabolomic profiling of patients with pre-diabetes demonstrated that the increase in GCDCA during an OGTT is reduced, and negatively correlates with fasting insulin.⁹⁸ In contrast, Vincent et al. demonstrated that patients with obesity and T2DM experience a higher peak change in total bile acids and in total glycine-conjugated bile acids compared with matched normoglycaemic controls when challenged with a standard meal.¹¹¹ Similarly, a recent study looking at OGTT and meals with differential fat content reported that in all but the high-fat meal, patients with T2DM experienced a higher area under the curve for postprandial total bile acids than the matched controls.²³

In terms of composition of the bile acid pool, obesity has been associated with a higher cholic acid content of the bile pool.¹⁰⁶ Similarly, insulin resistance has been associated with an increased fasting ratio of 12α-hydroxylated bile acids (cholic acid, DCA and derivatives) to non-12α hydroxylated forms (CDCA, LCA and other derivatives).^95,108 This has been attributed to a reduction in insulin stimulation of hepatic forkhead box protein O1, which ordinarily suppresses CYP8B1 and therefore decreases conversion of bile acid intermediates to cholic acid.¹¹² A recent study of patients with T2DM demonstrated that most fasting bile acid species were higher than in matched controls, and that postprandially patients with T2DM had higher 12α-hydroxylated bile acids with comparable CDCA and its derivatives.²³ Wewalka et al. reported a correlation between total taurine-conjugated species and insulin resistance,¹⁰⁷ with a trend towards higher fasting taurine–cholic acid but not glycine–cholic acid in patients with T2DM.

Plasma metabolomic profiling of non-diabetic patients with histologically confirmed non-alcoholic fatty liver compared with healthy age- and sex-matched controls revealed significantly higher fasting concentrations of conjugated bile acids.¹¹³ Similarly, higher fasting and postprandial excursions of circulating total and conjugated bile acids were found in a small study of patients with confirmed NASH.¹¹⁴ Potential confounders of both studies include the fact that although all volunteers were non-diabetic, patients with steatosis had higher BMI and higher indices of insulin resistance than controls. A further study of patients with liver impairments from all causes also demonstrated higher total and conjugated serum bile acids,²⁴ suggesting that these changes are common to all liver injury rather than specific to NAFL and insulin resistance.

As NAFL progresses to NASH and then cirrhosis, there is evidence that bile acid synthesis gene expression changes, with upregulation of CYP7B1 and thus promotion of the alternative pathway of bile acid synthesis.¹¹⁵ BAAT expression and taurine availability increase, resulting in a change in composition of hepatocyte bile acids towards taurine-conjugated species.¹¹⁵ Total hepatic bile acid content is higher in patients with steatohepatitis than in matched controls, whether of alcoholic or non-alcoholic origin.¹¹⁶

Contribution of the gut microbiome

The gut microbiota, which is an extraordinarily diverse and plastic community of symbiotic bacterial species, is responsible for biotransformation of primary to secondary bile acids as they pass through the gut. As bacterial enzymes that conjugate bile acids vary according to bacterial strain, the microbial community is a key determinant of bile acid pool size and composition.^44,117 Oral agents that alter the microbiome, such as probiotics, antibiotics and antioxidants, change bile acid profiles: mechanisms include changes in intestinal conjugation of bile acids and differential expression of hepatic and intestinal bile acid transporters.^118–120 Furthermore, bile acids themselves affect the composition of the gut microbiome, via direct detergent effects on bacteria as well as effects on intestinal mucosa integrity.¹²¹

Microbiome changes are well documented in association with NAFLD,^122,123 obesity and T2DM.¹²⁴ The mechanisms by which the microbiome influences metabolic health extend beyond its effects on bile acid transformation. For example, different bacterial communities produce different metabolites, which act as local signalling molecules with differential effects on mucosal inflammation, intestinal permeability and gut hormone production.¹²⁵ The relationships between metabolic disease, bile acids and the gut microbiota are therefore complex and interdependent.

Bile acid manipulation for metabolic diseases

Given the potentially beneficial metabolic actions of bile acids, there has been much interest in harnessing their effects as therapy for metabolic syndrome diseases. Bile acids, bile acid-binding resins and synthetic FXR and TGR5 agonists have been investigated for this purpose. Due to the complex negative feedback cycles involved in bile acid homeostasis, the use of these types of agents is not straightforward, as they may have variable and unpredictable effects on overall bile acid pool size and composition.⁶⁶ In part, the effect of treatment on circulating bile acids depends on pretreatment bile acid pool, which varies with the presence and/or severity of metabolic disease.

Bile acid-binding sequestrants

Bile acid-binding resins or sequestrants (BAS) are non-absorbable cationic polymers that bind bile acids in the gut and prevent their resorption. Use of these agents, which include colesevelam, cholestyramine and sevelamer, reduces the return of intestinal bile acids to the liver, thereby stimulating the synthesis of new bile acids from cholesterol.¹²⁶ Used as single agents or as part of combination therapy, BAS are well known to reduce lipidaemia and decrease coronary artery disease risk.¹²⁷

Colesevelam as an adjunct to other lipid-lowering therapies in patients with poorly controlled T2DM has been shown in several randomized controlled trials (RCTs) to reduce glycaemia and lipidaemia.^126,128 Colestimide as an add-on to lifestyle modification has been shown in an RCT to confer additional benefits for patients with NASH: better improvement in liver histology and transaminases, greater decrease in visceral fat and enhanced improvement in glycated haemoglobin (HbA1c).¹²⁹ Sevelamer has been shown in a mouse model of NAFLD to improve hepatic steatosis and inflammation in NASH by inhibiting FXR signalling¹³⁰; human trials are awaited. Colesevelam, however, has not been shown to confer the same benefits and has been associated with an increase in liver fat in both mice and patients with biopsy-proven NASH.^131,132

The exact mechanism of the positive metabolic effects of BAS is incompletely understood.^126,133 Up to eight weeks of treatment with colesevelam does not increase total bile acid pool size in either healthy volunteers or patients with T2DM, but doubles the cholic acid proportion of the pool.⁹⁵ Colesevelam treatment has also been shown to increase fasting and postprandial levels of incretin hormones glucagon-like peptide 1 and gastric inhibitory polypeptide.¹³⁴ The mechanism for this is likely due to the fact that BAS retain bile acids in the gut, allowing them to stimulate TGR5 receptor in the colon (in normal physiology, almost all bile acids are reabsorbed in the small intestine, with very few reaching the colon).¹³⁵ Differential binding affinities for different bile acid species may explain differences in clinical effect conferred by use of different BAS.¹²⁶

Bile acids

UDCA is used for the treatment of primary biliary cirrhosis, and in this context has been shown to activate anti-inflammatory hepatocyte pathways and improve liver function.¹³⁶ As a treatment for NASH, however, there have been several RCTs¹³⁷ with results that are insufficient for its recommendation by any of the major practice guidelines.¹³⁸ It is worth noting that UDCA is inactive at the FXR receptor at physiological concentrations.³⁸ CDCA has recently been demonstrated in mice on a high-fat diet (HFD) to decrease weight and improve glucose tolerance.¹³⁹

Synthetic drugs that target bile acid receptors

Due to the regulatory role of FXR stimulation on glucose and lipid metabolism, multiple FXR-specific agonists are in development.¹⁴⁰ CDCA is the most potent natural ligand for FXR³⁸; therefore, it has been used as the starting point for the development of synthetic FXR agonists. Obeticholic acid (OCA; INT747) is the best characterized of these. It is a synthetic 6α ethyl derivative of CDCA and a highly potent FXR agonist, and is administered as an oral tablet.

In a multicentre randomized control trial, patients with histologically confirmed non-cirrhotic NASH were treated with OCA or placebo for 72 weeks.¹⁴¹ Patients treated with OCA had significantly greater improvements in liver histology, including better reduction in steatosis, inflammation and fibrosis. They also had an approximate 2 kg reduction in weight and decreases in alanine aminotransferase and gamma glutamyltranspetidase, but an increase in aspartate aminotransferase. Patients treated with OCA experienced a rise in serum cholesterol and insulin resistance (as measured by homeostatic model assessment (HOMA)); they also experienced a higher incidence of pruritus than placebo.¹⁴¹ Clinical findings were similar to those of a shorter six-week study of patients with T2DM and NAFLD; however in this latter study, which used hyperinsulinaemic euglycaemic clamps, insulin sensitivity improved with OCA treatment.¹⁴² The finding of increased serum cholesterol is predictable, due to the suppression of bile acid synthesis by FXR activity; it is unclear at this stage if this effect is linked to adverse clinical outcomes. Pruritus may be due to cross-reactivity with the TGR5 receptor.⁸² The results of a phase III study of OCA in NASH with fibrosis are awaited.¹⁴⁰

A potential problem with systemic FXR agonism is that the effects appear to be strikingly different depending on the animal model studied. For example, the synthetic FXR agonist GW4064 improves glucose tolerance in wild-type and db/db mice,¹⁴³ but exacerbates weight gain and glucose intolerance, and decreases energy expenditure, in mice on a HFD.¹⁴⁴ This might be explained by different hepatic transcription pathways secondary to FXR stimulation in obese mice when compared with lean.¹⁴⁵ Furthermore, administration of GW4064 dramatically changes the bile acid pool size and composition¹⁴⁴; different starting bile acid pool size and composition in animals with metabolic disease compared with healthy counterparts may be altered in different ways.

One response to this issue is the development of non-steroidal FXR agonists. In contrast to OCA and other bile acid-derived compounds, an advantage of these is that they are expected not to undergo enterohepatic circulation and therefore have more predictable pharmacokinetics. GS-9674 and LJN452 are two such compounds currently in phase II clinical trials.¹⁴⁰

Another approach is an FXR intestine-specific agonist, for example fexaramine, which is a poorly absorbed oral agent and is therefore intestinally restricted. This has been found to reduce weight gain and improve glucose tolerance in diet-induced obese (DIO) mice.¹⁴⁶ Paradoxically, an intestinal FXR antagonist, glycine-β-MCA, has also been shown to improve metabolic phenotype of mice on a HFD.¹⁴⁷

TGR5 agonism is also beneficial for metabolic disease, primarily by increasing energy expenditure. The TGR5-specific agonist INT777 decreases weight in DIO mice, increases energy expenditure and decreases hepatic steatosis.^148,149

Finally, some compounds in development are dual agonists at both the FXR and TGR5 receptor. One such is INT767, which has been shown to improve steatohepatitis in obese diabetic mice over six weeks of treatment, despite no significant change in body weight or glucose tolerance.¹⁵⁰

Conclusion

Given the global pandemic of obesity and related disorders, and the escalating understanding of bile acids as powerful regulators of metabolism, this is a very exciting time for bile acid biology. Generally, the actions of bile acids are positive for metabolic health and include elimination of dietary cholesterol, stimulation of gut hormone release, increased energy expenditure, reduction of liver fat and inflammation and reduction of ER stress. Circulating bile acid levels are highly responsive to physiological and pathophysiological variables, which can make their assessment difficult. Nonetheless, most evidence suggests that both fasting and postprandial circulating levels are higher in metabolic disease. This could potentially represent a compensatory state where an increase in bile acids is a physiological response to alleviate further development of metabolic disease.

In terms of pharmacological use of bile acids and related compounds as therapy for metabolic diseases, the field is highly active with many new drugs being synthesized and trialled. One challenge is the tight homeostatic response to bile acid manipulation, which means that overall effect on pool size and composition of bile acids reaching target tissues is often difficult to predict. Furthermore, the activity of major bile acid receptor FXR appears to differ in different disease states, affecting the response to bile acid manipulation. Nonetheless, the powerful metabolic actions of bile acids and their generally good safety profile make them excellent therapeutic targets. Further developments in this field are eagerly anticipated.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7- HEALTH-2009– 241592 EuroCHIP grant and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the authors and not necessarily those of aforementioned funders, the NHS, the NIHR or the Department of Health. ER McGlone is also funded by the Medical Research Council with a clinical research training fellowship.

Ethical approval

Not applicable.

Guarantor

ERM.

Contributorship

Both authors conceived the topic. ERM wrote the first draft of the article, which was reviewed by SRB. Both authors approved the final version of the article.

References

World Health Organization. Obesity and overweight, www.who.intnews-roomfact-sheetsdetailobesity-and-overweight (2018, accessed 18 August 2018).

Public Health England. Adult obesity and type 2 diabetes, www.gov.uk/government/publications/adult-obesity-and-type-2-diabetes (2014, accessed 18 August 2018).

Younossi

Koenig

Abdelatif

et al . Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73–84.

Russell

DW.

The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003; 72: 137–174.

Hofmann

Hagey

Krasowski

MD.

Bile salts of vertebrates: structural variation and possible evolutionary significance. J Lipid Res 2010; 51: 226–246.

Hofmann

Hagey

LR.

Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci 2008; 65: 2461–2483.

Monte

Marin

JJG

Antelo

et al . Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol 2009; 15: 804–816.

Eggert

Bakonyi

Hummel

Enzymatic routes for the synthesis of ursodeoxycholic acid. J Biotechnol 2014; 191: 11–21.

Ferdinandusse

Denis

Faust

et al . Bile acids: the role of peroxisomes. J Lipid Res 2009; 50: 2139–2147.

10.

Zwicker

Agellon

LB.

Transport and biological activities of bile acids. Int J Biochem Cell Biol 2013; 45: 1389–1398.

11.

Ishibashi

Schwarz

Frykman

et al . Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation. J Biol Chem 1996; 271: 18017–18023.

12.

Schwarz

Lund

Setchell

et al . Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase. J Biol Chem 1996; 271: 18024–18031.

13.

Duane

Javitt

NB.

27-hydroxycholesterol: production rates in normal human subjects. J Lipid Res 1999; 40: 1194–1199.

14.

Björkhem

Lütjohann

Breuer

et al . Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro. J Biol Chem 1997; 272: 30178–30184.

15.

Björkhem

Diczfalusy

Lütjohann

Removal of cholesterol from extrahepatic sources by oxidative mechanisms. Curr Opin Lipidol 1999; 10: 161–165.

16.

Babiker

Andersson

Lindblom

et al . Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin. J Lipid Res 1999; 40: 1417–1425.

17.

Zhang

Chiang

JY.

Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression. J Biol Chem 2001; 276: 41690–41699.

18.

Sievänen

Exploitation of bile acid transport systems in prodrug design. Molecules 2007; 12: 1859–1889.

19.

Swann

Want

Geier

et al . Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA 2011; 108: 4523–4530.

20.

Sayin

Wahlström

Felin

et al . Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013; 17: 225–235.

21.

Mooranian

Negrulj

Arfuso

et al . The effect of a tertiary bile acid, taurocholic acid, on the morphology and physical characteristics of microencapsulated probucol: potential applications in diabetes: a characterization study. Drug Deliv and Transl Res 2015; 5: 511–522.

22.

Hofmann

Hagey

LR.

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J Lipid Res 2014; 55: 1553–1595.

23.

Sonne

van Nierop

Kulik

et al . Postprandial plasma concentrations of individual bile acids and FGF-19 in patients with type 2 diabetes. J Clin Endocrinol Metab 2016; 101: 3002–3009.

24.

Luo

Aubrecht

et al . Assessment of serum bile acid profiles as biomarkers of liver injury and liver disease in humans. PLoS One 2018; 13: e0193824.

25.

Beglinger

Hildebrand

Adler

et al . Postprandial control of gallbladder contraction and exocrine pancreatic secretion in man. Eur J Clin Invest 1992; 22: 827–834.

26.

Gälman

Angelin

Rudling

Pronounced variation in bile acid synthesis in humans is related to gender, hypertriglyceridaemia and circulating levels of fibroblast growth factor 19. J Intern Med 2011; 270: 580–588.

27.

Dawson

Haywood

Craddock

et al . Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J Biol Chem 2003; 278: 33920–33927.

28.

Rao

Haywood

Craddock

et al . The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis. Proc Natl Acad Sci USA 2008; 105: 3891–3896.

29.

Stieger

The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol 2011; 201: 205–259.

30.

Lombardo

Bile salt-dependent lipase: its pathophysiological implications. Biochim Biophys Acta 2001; 1533: 1–28.

31.

Thompson

GR.

Absorption of fat-soluble vitamins and sterols, https://jcp.bmj.com/content/jclinpath/s3-5/1/85.full.pdf (1971, 5 accessed September 2018).

32.

Saeed

Hoekstra

Hoeke

et al . The interrelationship between bile acid and vitamin A homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862: 496–512.

33.

Lofland

Clarkson

St Clair

et al . Studies on the regulation of plasma cholesterol levels in squirrel monkeys of two genotypes. J Lipid Res 1972; 13: 39–47.

34.

Charach

Grosskopf

Rabinovich

et al . The association of bile acid excretion and atherosclerotic coronary artery disease. Therap Adv Gastroenterol 2011; 4: 95–101.

35.

Charach

Argov

Geiger

et al . Diminished bile acids excretion is a risk factor for coronary artery disease: 20-year follow up and long-term outcome. Therap Adv Gastroenterol 2018; 11: 1756283X17743420.

36.

Agellon

LB.

Chapter 16 Metabolism and function of bile acids. In: Biochemistry of lipids, lipoproteins and membranes. 4th ed. Amsterdam: Elsevier, 2002, pp.433–448.

37.

Noel

Still

Argyropoulos

et al . Bile acids, FXR, and metabolic effects of bariatric surgery. J Obes 2016; 3: 4390254–4390258.

38.

Lefebvre

Cariou

Lien

et al . Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009; 89: 147–191.

39.

Huber

Murphy

Miao

et al . Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 2002; 290: 35–43.

40.

Vaquero

Monte

Dominguez

et al . Differential activation of the human farnesoid X receptor depends on the pattern of expressed isoforms and the bile acid pool composition. Biochem Pharmacol 2013; 86: 926–939.

41.

Kong

Zhu

et al . Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice. Toxicol Appl Pharmacol 2013; 272: 299–305.

42.

Zollner

Wagner

Fickert

et al . Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver. Am J Physiol Gastrointest Liver Physiol 2005; 289: G798–G805.

43.

Plass

JRM

Mol

Heegsma

et al . Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology 2002; 35: 589–596.

44.

Mazuy

Helleboid

Staels

et al . Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci 2015; 72: 1631–1650.

45.

Schwarz

Russell

Dietschy

et al . Marked reduction in bile acid synthesis in cholesterol 7alpha-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia. J Lipid Res 1998; 39: 1833–1843.

46.

Li-Hawkins

Gåfvels

Olin

et al . Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J Clin Invest 2002; 110: 1191–1200.

47.

Song

K-H

Owsley

et al . Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology 2009; 49: 297–305.

48.

Kong

Wang

Chiang

JYL

et al . Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 2012; 56: 1034–1043.

49.

Lan

Morgan

Rahmouni

et al . FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab 2017; 26: 709–718.e3.

50.

Claudel

Inoue

Barbier

et al . Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology 2003; 125: 544–555.

51.

Kast

Nguyen

Sinal

et al . Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 2001; 15: 1720–1728.

52.

Mak

Kast-Woelbern

Anisfeld

et al . Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J Lipid Res 2002; 43: 2037–2041.

53.

Laffitte

Kast

Nguyen

et al . Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor. J Biol Chem 2000; 275: 10638–10647.

54.

Anisfeld

Kast-Woelbern

Meyer

et al . Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor. J Biol Chem 2003; 278: 20420–20428.

55.

Sirvent

Claudel

Martin

et al . The farnesoid X receptor induces very low density lipoprotein receptor gene expression. FEBS Lett 2004; 566: 173–177.

56.

Lambert

Amar

MJA

Guo

et al . The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem 2003; 278: 2563–2570.

57.

Kong

Luyendyk

Tawfik

et al . Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 2009; 328: 116–122.

58.

Saha

Chan

et al . Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 2006; 116: 1102–1109.

59.

Zhu

Liu

Zhang

et al . Fatty liver diseases, bile acids, and FXR. Acta Pharm Sin B 2016; 6: 409–412.

60.

Aguilar-Olivos

Carrillo-Córdova

Oria-Hernández

et al . The nuclear receptor FXR, but not LXR, up-regulates bile acid transporter expression in non-alcoholic fatty liver disease. Ann Hepatol 2015; 14: 487–493.

61.

Gadaleta

Cariello

Sabbà

et al . Tissue-specific actions of FXR in metabolism and cancer. Biochim Biophys Acta 2015; 1851: 30–39.

62.

Kim

D-H

Xiao

Kwon

et al . A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. Embo J 2015; 34: 184–199.

63.

Cariou

van Harmelen

Duran-Sandoval

et al . The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 2006; 281: 11039–11049.

64.

Kurosu

Choi

Ogawa

et al . Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282: 26687–26695.

65.

Düfer

Hörth

Wagner

et al . Bile acids acutely stimulate insulin secretion of mouse β-cells via farnesoid X receptor activation and K(ATP) channel inhibition. Diabetes 2012; 61: 1479–1489.

66.

Düfer

Hörth

Krippeit-Drews

et al . The significance of the nuclear farnesoid X receptor (FXR) in β cell function. Islets 2012; 4: 333–338.

67.

Kawamata

Fujii

Hosoya

et al . A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003; 278: 9435–9440.

68.

Duboc

Taché

Hofmann

AF.

The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 2014; 46: 302–312.

69.

Poole

Godfrey

Cattaruzza

et al . Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil 2010; 22: 814–825, e227–e228.

70.

Lavoie

Balemba

Godfrey

et al . Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of KATP channels. J Physiol 2010; 588: 3295–3305.

71.

Keitel

Görg

Bidmon

et al . The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 2010; 58: 1794–1805.

72.

Kuhre

Wewer Albrechtsen

Larsen

et al . Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab 2018; 11: 84–95.

73.

Keitel

Reinehr

Gatsios

et al . The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 2007; 45: 695–704.

74.

Keitel

Cupisti

Ullmer

et al . The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 2007; 50: 861–870.

75.

Holmstrom

Kir

et al . The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 2011; 25: 1066–1071.

76.

Adrian

Gariballa

Parekh

et al . Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers. Diabetologia 2012; 55: 2343–2347.

77.

Brighton

Rievaj

Kuhre

et al . Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 2015; 156: 3961–3970.

78.

Watanabe

Houten

Mataki

et al . Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439: 484–489.

79.

Calmus

Guechot

Podevin

et al . Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes. Hepatology 1992; 16: 719–723.

80.

Pols

TWH

Nomura

Harach

et al . TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 2011; 14: 747–757.

81.

Alemi

Poole

Chiu

et al . The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 2013; 144: 145–154.

82.

Alemi

Kwon

Poole

et al . The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123: 1513–1530.

83.

Trottier

Białek

Caron

et al . Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study. Dig Liver Dis 2012; 44: 303–310.

84.

Foufelle

Fromenty

Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol Res Perspect 2016; 4: e00211.

85.

Ozcan

Cao

Yilmaz

et al . Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457–461.

86.

Cnop

Foufelle

Velloso

LA.

Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 2012; 18: 59–68.

87.

Ozcan

Yilmaz

Ozcan

et al . Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006; 313: 1137–1140.

88.

Xie

Cai

et al . Tauroursodeoxycholic acid inhibits endoplasmic reticulum stress, blocks mitochondrial permeability transition pore opening, and suppresses reperfusion injury through GSK-3ß in cardiac H9c2 cells. Am J Transl Res 2016; 8: 4586–4597.

89.

Cummings

Bettaieb

Graham

et al . Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats. Dis Model Mech 2013; 6: 443–456.

90.

Berger

Haller

Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells. Biochem Biophys Res Commun 2011; 409: 610–615.

91.

Sarafian

Lewis

Pechlivanis

et al . Bile acid profiling and quantification in biofluids using ultra-performance liquid chromatography tandem mass spectrometry. Anal Chem 2015; 87: 9662–9670.

92.

Humbert

Maubert

Wolf

et al . Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients. J Chromatogr B Analyt Technol Biomed Life Sci 2012; 899: 135–145.

93.

Angelin

Björkhem

Einarsson

et al . Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum. J Clin Invest 1982; 70: 724–731.

94.

Houten

Watanabe

Auwerx

Endocrine functions of bile acids. Embo J 2006; 25: 1419–1425.

95.

Brufau

Stellaard

Prado

et al . Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology 2010; 52: 1455–1464.

96.

Glicksman

Pournaras

Wright

et al . Postprandial plasma bile acid responses in normal weight and obese subjects. Ann Clin Biochem 2010; 47: 482–484.

97.

Matysik

Martin

Bala

et al . Bile acid signaling after an oral glucose tolerance test. Chem Phys Lipids 2011; 164: 525–529.

98.

Shaham

Wei

Wang

et al . Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol 2008; 4: 214.

99.

Zhao

Peter

Fritsche

et al . Changes of the plasma metabolome during an oral glucose tolerance test: is there more than glucose to look at? Am J Physiol Endocrinol Metab 2009; 296: E384–E393.

100.

Frommherz

Bub

Hummel

et al . Age-related changes of plasma bile acid concentrations in healthy adults – results from the cross-sectional KarMeN study. PLoS One 2016; 11: e0153959.

101.

Lundåsen

Gälman

Angelin

et al . Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 2006; 260: 530–536.

102.

Reihnér

Björkhem

Angelin

et al . Bile acid synthesis in humans: regulation of hepatic microsomal cholesterol 7 alpha-hydroxylase activity. Gastroenterology 1989; 97: 1498–1505.

103.

Gälman

Angelin

Rudling

Bile acid synthesis in humans has a rapid diurnal variation that is asynchronous with cholesterol synthesis. Gastroenterology 2005; 129: 1445–1453.

104.

Gälman

Matasconi

Persson

et al . Age-induced hypercholesterolemia in the rat relates to reduced elimination but not increased intestinal absorption of cholesterol. Am J Physiol Endocrinol Metab 2007; 293: E737–E742.

105.

Gälman

Miquel

Pérez

et al . Bile acid synthesis is increased in Chilean Hispanics with gallstones and in gallstone high-risk Mapuche Indians. Gastroenterology 2004; 126: 741–748.

106.

Cariou

Chetiveaux

Zaïr

et al . Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults. Nutr Metab (Lond) 2011; 8: 48.

107.

Wewalka

Patti

M-E

Barbato

et al . Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin. J Clin Endocrinol Metab 2014; 99: 1442–1451.

108.

Haeusler

Astiarraga

Camastra

et al . Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids. Diabetes 2013; 62: 4184–4191.

109.

Sun

Zhang

Wang

et al . Insulin resistance is associated with total bile acid level in type 2 diabetic and nondiabetic population: a cross-sectional study. Medicine (Baltimore) 2016; 95: e2778.

110.

Ahmad

Pfalzer

Kaplan

LM.

Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity. Int J Obes (Lond) 2013; 37: 1553–1559.

111.

Vincent

Omar

Ghozlan

et al . Higher circulating bile acid concentrations in obese patients with type 2 diabetes. Ann Clin Biochem 2013; 50: 360–364.

112.

Haeusler

Pratt-Hyatt

Welch

et al . Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia. Cell Metab 2012; 15: 65–74.

113.

Kalhan

Guo

Edmison

et al . Plasma metabolomic profile in nonalcoholic fatty liver disease. Metab Clin Exp 2011; 60: 404–413.

114.

Ferslew

Xie

Johnston

et al . Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Dig Dis Sci 2015; 60: 3318–3328.

115.

Lake

Novak

Shipkova

et al . Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease. Toxicol Appl Pharmacol 2013; 268: 132–140.

116.

Aranha

Cortez-Pinto

Costa

et al . Bile acid levels are increased in the liver of patients with steatohepatitis. Eur J Gastroenterol Hepatol 2008; 20: 519–525.

117.

Staley

Weingarden

Khoruts

et al . Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol 2017; 101: 47–64.

118.

Jiang

Krausz

et al . Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013; 4: 2384.

119.

Degirolamo

Rainaldi

Bovenga

et al . Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep 2014; 7: 12–18.

120.

Zhang

Limaye

Renaud

et al . Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice. Toxicol Appl Pharmacol 2014; 277: 138–145.

121.

Trauner

Fickert

Tilg

Bile acids as modulators of gut microbiota linking dietary habits and inflammatory bowel disease: a potentially dangerous liaison. Gastroenterology 2013; 144: 844–846.

122.

Mouzaki

Comelli

Arendt

et al . Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013; 58: 120–127.

123.

Schnabl

Brenner

DA.

Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014; 146: 1513–1524.

124.

Tilg

Moschen

AR.

Microbiota and diabetes: an evolving relationship. Gut 2014; 63: 1513–1521.

125.

Upadhyaya

Banerjee

Type 2 diabetes and gut microbiome: at the intersection of known and unknown. Gut Microbes 2015; 6: 85–92.

126.

Staels

Handelsman

Fonseca

Bile acid sequestrants for lipid and glucose control. Curr Diab Rep 2010; 10: 70–77.

127.

Insull

Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med J 2006; 99: 257–273.

128.

Ooi

Loke

SC.

Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review. Diabet Med 2014; 31: 2–14.

129.

Taniai

Hashimoto

Tobari

et al . Treatment of nonalcoholic steatohepatitis with colestimide. Hepatol Res 2009; 39: 685–693.

130.

McGettigan

McMahan

Luo

et al . Sevelamer improves steatohepatitis, inhibits liver and intestinal farnesoid x receptor (FXR), and reverses innate immune dysregulation in a mouse model of non-alcoholic fatty liver disease. J Biol Chem 2016; 291: 23058–23067.

131.

T-A

Chen

Changchien

et al . Effect of colesevelam on liver fat quantified by magnetic resonance in nonalcoholic steatohepatitis: a randomized controlled trial. Hepatology 2012; 56: 922–932.

132.

Herrema

Meissner

van Dijk

et al . Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor- and liver X receptor alpha-controlled metabolic pathways in mice. Hepatology 2010; 51: 806–816.

133.

Schwartz

Lai

Y-L

et al . The effect of colesevelam hydrochloride on insulin sensitivity and secretion in patients with type 2 diabetes: a pilot study. Metab Syndr Relat Disord 2010; 8: 179–188.

134.

Beysen

Murphy

Deines

et al . 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 2012; 55: 432–442.

135.

Harach

Pols

TWH

Nomura

et al . TGR5 potentiates GLP-1 secretion in response to anionic exchange resins. Sci Rep 2012; 2: 430.

136.

Chiang

JYL.

Bile acid metabolism and signaling in liver disease and therapy. Liver Res 2017; 1: 3–9.

137.

Xiang

Chen

Y-P

K-F

et al . The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol 2013; 13: 140.

138.

Sumida

Yoneda

Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 2018; 53: 362–376.

139.

Chen

Yan

Guo

et al . Chenodeoxycholic acid attenuates high-fat diet-induced obesity and hyperglycemia via the G protein-coupled bile acid receptor 1 and proliferator-activated receptor γ pathway. Exp Ther Med 2017; 14: 5305–5312.

140.

Sepe

Distrutti

Fiorucci

et al . Farnesoid X receptor modulators 2014-present: a patent review. Expert Opin Ther Pat 2018; 28: 351–364.

141.

Neuschwander-Tetri

Loomba

Sanyal

et al . Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956–965.

142.

Mudaliar

Henry

Sanyal

et al . Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 574–582.e1.

143.

Zhang

Lee

Barrera

et al . Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci 2006; 103: 1006–1011.

144.

Watanabe

Horai

Houten

et al . Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem 2011; 286: 26913–26920.

145.

Lee

Seok

et al . Genomic analysis of hepatic farnesoid X receptor binding sites reveals altered binding in obesity and direct gene repression by farnesoid X receptor in mice. Hepatology 2012; 56: 108–117.

146.

Fang

Suh

Reilly

et al . Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015; 21: 159–165.

147.

Gonzalez

Jiang

Patterson

AD.

An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 2016; 151: 845–859.

148.

de Oliveira

Gilglioni

de Boer

et al . Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice. Biochim Biophys Acta 2016; 1862: 2054–2062.

149.

Pellicciari

Gioiello

Macchiarulo

et al . Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J Med Chem 2009; 52: 7958–7961.

150.

McMahan

Wang

Cheng

et al . Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 2013; 288: 11761–11770.

Bile acids and the metabolic syndrome

Abstract

Keywords

Introduction

Bile acid chemistry

Bile acid structure

Primary bile acid biosynthesis

Bile acid classification

Enterohepatic circulation of bile acids

Bile acid transport

Metabolic actions of bile acids (Table 1)

Lipid digestion and absorption

Actions of bile acids mediated by FXR

Actions mediated by TGR5

Reduction of endoplasmic stress

Changes in bile acid circulation in health and disease

Circulating bile acid fluctuations in metabolic health

Fluctuations in bile acid synthesis

Bile acid homeostasis in obesity and diseases of insulin resistance

Contribution of the gut microbiome

Bile acid manipulation for metabolic diseases

Bile acid-binding sequestrants

Bile acids

Synthetic drugs that target bile acid receptors

Conclusion

Footnotes

Declaration of conflicting interests

Funding

Ethical approval

Guarantor

Contributorship

References