Review Article: The Emerging Interplay Among the Gastrointestinal Tract, Bile Acids and Incretins in the Pathogenesis of Diabetes and Non-alcoholic Fatty Liver Disease

A. Zarrinpar; R. Loomba

Disclosures

Aliment Pharmacol Ther. 2012;36(10):909-921. 

In This Article

The Role of Bile Acids in Glucose Homoeostasis

Recent studies show that bile acids play a much larger role in glucose homoeostasis than previously thought. After being released by the gallbladder into the intestines, nearly all of the bile acids (95%) get reabsorbed in the terminal ileum, decreasing the need for de novo bile acid synthesis.[127,128] Hence, there is frequent cycling of the bile acids (i.e. bile acid pool) between the intestines and the liver in the enterohepatic circulation. Bile acids are endogenous ligands to several receptors, including farnesoid X receptor (FXR) and pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D receptor (VDR) and the G-protein-coupled receptor TGR5. Through various signalling pathways, bile acids regulate cholesterol, fasting and mealtime glucose, and metabolism/energy homoeostasis as well as their own synthesis and blood levels in the enterohepatic circulation.[127,128] The composition of the bile acid pool has been shown to be altered in patients with T2DM.[129] In this section, we will discuss two bile acid signalling pathways, the FXR- and TGR5-mediated changes in homoeostasis, in detail.

Characterisation of several nuclear receptors has led to a better understanding of how hepatic metabolism can be altered by nutrition from the gut. Nuclear receptors have a ligand-binding domain and a DNA-binding domain. Once activated by a ligand, they can induce a transcriptional change in target genes. They provide important means through which cells can maintain homoeostasis in response to changes in their environmental stimuli, such as diet. Studies of several nuclear receptors that were previously thought to be orphaned now reveal that they respond to metabolites such as fatty acids and oxysterols, in addition to digestive enzymes, such as bile acids.[130,131] FXR was a previously orphaned nuclear receptor until bile acids were discovered to be their ligands.[132]

FXR is primarily found in the liver, kidney and intestines, and overall inhibits hepatic de novo bile acid production.[133–135] Bile acids are produced when cholesterol is oxidised in the liver. The 'classical' pathway of bile acid production is via 7-α hydroxylation of cholesterol by a rate-limiting enzyme, cholesterol 7-α hydroxylase (CYP7A1). An 'alternate' pathway, with 27-hydroxylase in the mitochondria of extrahepatic tissues (e.g. endothelial cells), can also produce bile acids. FXR inhibits de novo bile acid formation with the induction of small heterodimer partner (SHP). SHP plays an essential role in feedback regulation of bile acid biosynthesis through repression of CYP7A1 by inhibiting two nuclear receptors: liver receptor homolog-1 (LRH-1) and hepatocyte nuclear factor-4α (HNF-4α; see Figure 1).[137] CYP7A1 is a critical regulatory gene in bile acid synthesis. By inhibiting CYP7A1, FXR inhibits the classic pathway of de novo bile acid formation and moves this process to extrahepatic tissues.

Figure 1.

Potential mechanism(s) of action for the glycaemic effects of a bile acid sequestrant. FGF, fibroblast growth factor; FGFR, FGF receptor; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; GR, glucocorticoid receptor; HNF-4, hepatocyte nuclear factor-4; JNK, c-Jun N-terminal kinase; LRH-1, liver receptor homolog-1; SHP, small heterodimer partner. Reprinted with permission from Wright WL.136

Earlier studies have shown that FXR plays an important role in lipoprotein metabolism,[138] and FXR knockout mice exhibited elevated plasma triglyceride and cholesterol levels as well as steatohepatitis.[139] More recent studies have shown that FXR is also important to glucose homoeostasis. FXR knockout mice showed impaired glucose tolerance and decreased insulin sensitivity.[140] The role of FXR in glucose homoeostasis was further bolstered when FXR synthetic agonists or induced overexpression of FXR repressed hepatic gluconeogenesis and enhanced glycogen synthesis and storage, inducing an overall lower blood glucose level.[135] FXR activation induces expression and secretion of fibroblast growth factor (FGF)19 and FGF21 in the intestine (Figure 1).[141] Administration of FGF19 and FGF21 to diet-induced obesity mice increased their energy expenditure and caused weight loss and, as a result, improved insulin sensitivity.[142,143] Alterations in bile salts passing through the intestines have strong effects on metabolism by modulating FXR-mediated FGF19 and FGF21 secretion. Because FXR agonists can play a role in both treating steatohepatitis and improving glucose homoeostasis, they have become an area of intense research as potential pharmacotherapy for T2DM and non-alcoholic fatty liver disease.

Another mechanism through which bile acids affect glucose metabolism is a novel cell surface G-protein-coupled receptor, TGR5 (Figure 1).[144,145] TGR5 is found in brown adipose tissue, the liver and intestines.[146] Bile acid stimulation of TGR5 increases intracellular cAMP. The effect of this rise in cAMP differs depending on the cell expressing TGR5. For example, in brown adipose tissue, bile acid induction of TGR5 results in a cascade of reactions that eventually converts inactive thyroid hormone (T4) to its active form (T3), hence modulating energy expenditure.[147] The role of bile acids on glucose homoeostasis was reinforced when studies showed that murine enteroendocrine cell lines, when activated by bile acids, secreted GLP-1 via activation of TGR5.[148]

Whether TGR5 actually plays a role in glucose homoeostasis was not elucidated until a few years later. Thomas et al. showed that the TGR5 agonist INT-777 (Intercept Pharmaceuticals, Inc., New York, NY, USA; a bile acid mimetic) induced GLP-1 secretion in human L-cell lines by increasing intracellular levels of cAMP and altering the ATP/adenosine diphosphate (ADP) ratio and causing an influx of calcium, which, in turn, induced GLP-1 secretion.[149] TGR5 overexpression potentiated GLP-1 secretion, whereas TGR5 RNA interference blunted it. Activation of TGR5 by INT-777 in obese mice also prevented weight gain, preserved pancreatic function, and improved insulin sensitivity.

Given these findings, a more complete picture of the normal physiology of meal ingestion and bile acid glucose homoeostasis can be formed. After ingestion of a meal, the gallbladder contracts and the amount of bile acids in the intestine increases. This, in turn, causes nutrient-induced secretion of GLP-1 from L cells via activation of TGR5. T2DM dampens gallbladder motility, leading to reduced flow of bile acids to the intestine. With reduced bile acids, there is decreased activation of TGR5 in L cells of the intestine, leading to lower secretion of GLP-1 and poor glucose homoeostasis with decreased insulin secretion.[150]

Despite growing literature on the direct role that bile acids can play in increasing GLP-1 by activating TGR5 in L cells, there is a paradox in that the main therapeutic target thus far has been to diminish the amount that can act in the terminal ileum. Bile acid sequestrants, such as colesevelam hydrochloride (Daiichi Sankyo, Inc., Parsippany, NJ, USA), form non-absorbable complexes with bile acids in the gastrointestinal tract preventing reabsorption and promoting their faecal excretion.[146] Although bile acid sequestrants have been used for control of hyperlipidaemia for decades, they have shown to be effective in improving glycaemic control in patients with T2DM. Studies show that colesevelam resulted in a reduction of haemoglobin A1C of 0.5% when compared with placebo.[151–153] Significantly greater reductions in fasting glucose levels were seen following 16–26 weeks of treatment with colesevelam compared with placebo, in addition to insulin-, metformin-, and sulphonylurea-based therapy, further suggesting that bile acids play a role in fasting plasma glucose control.

An explanation for this paradox was proposed by Hofmann in a letter to the journal Hepatology.[154] Passage of fatty acids into the ileum (because micellar solubilisation is not yet completed in the jejunum) may lead to increased GLP-1 release from the ileal L cells. This is supported by the finding that administration of colesevelam to rats with diet-induced obesity and insulin resistance led to improvements in glucose tolerance and insulin resistance that were accompanied by increased plasma GLP-1 levels; changes in these parameters were not seen in rats administered SC-435 (which decreases bile absorption in the ileum, leading to inactivation of FXR).[155] Similarly, in patients with T2DM, the addition of colesevelam to a regimen comprising a sulphonylurea and/or metformin was associated with improvements in glycaemic control together with increased plasma levels of GLP-1 and GIP, compared with placebo.[156] This could be the mechanism through which glycaemic control improves in patients with T2DM with the bile acid sequestrant colesevelam. In addition, this mechanism could explain improvements in glycaemic control following intestinal transposition or other bariatric surgery, as discussed in the next section.

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