Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs

Abstract

Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research.

Fig. 1 |. Bile acid synthesis, modification and physicochemical properties.

a | Bile acid (BA) synthesis occurs only in the liver. In the classic pathway of BA synthesis, cholesterol is hydroxylated in the 7α position by the enzyme CYP7A1. Alternatively, cholesterol is first converted to an oxysterol prior to being 7α-hydroxylated by the enzymes CYP7B1 or CYP39A1. These oxysterols can arise in the liver, through the enzyme CYP27A1, or they can arise in other cells — such as macrophages via CYP27A1 or brain via CYP46A1 — then travel to the liver. After the initial step, which is considered rate-limiting, over a dozen enzymatic reactions proceed to generate the primary BA molecule chenodeoxycholic acid (CDCA). An intermediate in BA synthesis, 7α-hydroxy-4-cholesten-3-one, can undergo 12α-hydroxylation by the enzyme CYP8B1 and subsequently proceed through the additional steps. This process results in the generation of the second primary BA found in humans, cholic acid (CA). BAs are conjugated to an amino acid such as glycine (G) and secreted into the bile. BAs enter the duodenum directly or are stored in the gallbladder until postprandial gallbladder contraction. Most BAs are reabsorbed from the terminal ileum by the active transporter apical sodium-dependent bile acid transporter (ASBT). A minor fraction travel into the colon where they can be deconjugated and dehydroxylated by gut microorganisms, producing BAs that can be passively absorbed. From the portal vein, BAs are efficiently taken up into hepatocytes and recycled. A small fraction enter the systemic circulation. b | The major BA species found in humans and mice. c | Schematic demonstrating the amphipathic nature of BAs. *αMCA, βMCA and ωMCA are abundant in mice and rats but not humans.

Fig. 2 |. Bile acid composition.

a | Average bile acid (BA) composition in human biliary bile (left) and in enterohepatic tissues (including bile) of wild-type mice (right). Human biliary bile data are averages from REFs^–. Mouse BA pool data are averages from 58 wild-type mice across multiple studies including own published and unpublished studies. TMCA represents the sum of taurine-conjugated α-, β- and ω-muricholic acids (MCA). b | Effects of genetic knockouts^,,– and pharmacological treatments^,,, on mouse BA composition. Data for each BA species are the sum of conjugated and unconjugated BAs, and were calculated as (the percentage in the experimental pool/the percentage in the control pool). PX20606 and GW4064 are farnesoid X receptor (FXR) agonists. Fexaramine is a gut-restricted FXR agonist. In germ-free mice, no unconjugated BAs are detected. CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; GUDCA, glycoursodeoxycholic acid; i.e.-FXR, intestine epithelium-specific FXR knockout; L-FXR, liver-specific FXR knockout; LCA, lithocholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid.

Fig. 3 |. Effects of bile acids on metabolic processes throughout the body.

The primary sites of bile acid (BA) function are the liver and intestine, which are enriched in BAs and BA receptors. Through their ability to facilitate secretion of hormones such as glucagon-like peptide 1 (GLP1), fibroblast growth factor 19 (FGF19) and others, BAs can indirectly affect other tissues, including the brain. Furthermore, low levels of BAs are found in the systemic circulation, potentially enabling direct effects of BAs in tissues throughout the body. (R) indicates that supporting data were mostly from rodents; (H) indicates that supporting data were from humans, human cells or purified human proteins. Data were originally presented in the following effects in the central nervous system (CNS): peripheral glucose disposal (R), energy expenditure (R), and food intake (R); effects in islets: endoplasmic reticulum (ER) stress^, (R), and insulin secretion (R); effects in the liver: gluconeogenic gene expression^, (R), glycolytic gene expression^, (R, H), glycogen synthesis (R), hepatic triglyceride metabolism (R), hepatic lipotoxicity (R), and lipoprotein turnover^, (R, H); effects in adipose tissue: immune cell infiltration (R), and thermogenesis; effects in the gut: lipid absorption^,, (R), vitamin absorption (R, H), glucose absorption (R), ceramide production^, (R), N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) activity^, (purified human protein), GLP1 secretion^–, (R, H), peptide YY (PYY) secretion^, (R, H), and FGF19 secretion (R, H); and effects in skeletal muscle: lipotoxicity (R).

Fig. 4 |. Physiological and pathological conditions and therapies that influence bile acids.

An individual’s total levels of bile acids (BAs), levels in selected tissues such as the gut or plasma, and the composition of those bile acid species can each influence bile acid functions. These include functions mediated by receptors such as FXR and TGR5, as well as receptor-independent effects, such as nutrient absorption. Green boxes represent conditions, medications and interventions that can affect BAs. Solid lines represent known pathways that affect and/or are affected by BAs. Dotted lines represent potential pathways. ASBT, apical sodium-dependent bile acid transporter; TUDCA, tauroursodeoxycholic acid.