Sterols: 5. Bile Acids and Alcohols
The bile acids (mainly C24 but also C27) are the end products of cholesterol catabolism in animals, and their best-known functions are to act as powerful detergents or emulsifying agents in the intestines to aid the digestion and absorption of fatty acids, monoacylglycerols and other fatty products and to prevent the precipitation of cholesterol in bile. In addition, it is now recognized that they are involved as signalling molecules in the regulation of multiple biological reactions, especially in intestinal epithelial cells, the interface between the body and the luminal contents, where they are primary effectors of a host of responses via interactions with specific receptors, including suppression of their own synthesis in the liver. They also interact with receptors in liver cells and other extrahepatic tissues to influence vital metabolic processes.
Many different bile acids and alcohols occur in nature, often dependent on the animal species, presumably because multiple enzymatic pathways have evolved to convert cholesterol into these highly water-soluble, amphipathic molecules. The nomenclature is complex for historical reasons; many were given trivial names in the 19th century long before their structures were determined, and for example, nitrogen-free cholic acid was isolated as long ago as 1838. Although Heinrich Wieland obtained the 1927 Nobel Prize in Chemistry for his work on bile acids, the correct structure of the steroid nucleus was not determined until 1932 by the X-ray diffraction studies of Desmond Bernal, incidentally the first application of this technique to a biological problem.
1. Structures and Occurrence
Bile acids are family of steroids with a core structure of seventeen carbon atoms arranged in four fused rings, i.e., three cyclohexane rings (rings A-C) and one cyclopentane ring (ring D), together with a five or eight carbon side-chain terminating in a carboxylic acid group (or hydroxyl in the bile alcohols). In addition, they contain hydroxyl groups at positions C3, C7 and C12, and hydrophobic methyl groups at in positions C18 and C19. In contrast to most sterols, the A and B rings junction of bile acids, has a cis or chair configuration. They are sometimes termed 'cholanoids' or 'cholestanoids' and are usually subdivided into three main classification groups, i.e., C27 bile alcohols, C27 bile acids and C24 bile acids. The C27 bile alcohols and acids contain the C8 side chain of cholesterol, while the C24 bile acids have a truncated C5 side chain. At the last count, 84 distinct unconjugated bile acids and 25 bile alcohols were identified in vertebrates. The trivial names in common use are derived from cholic acid, the first bile acid to be fully characterized, with an element added that is derived from either the chemical structure or the primary animal source.
In mammals, C24 bile acids predominate and they are major components of bile amounting to about 12% of the total (with roughly 4% phospholipids and 1% cholesterol). In non-mammalian vertebrates, such as fish and reptiles, bile alcohols (non-acidic) are formed, while invertebrates do not produce bile acids or alcohols. During vertebrate evolution, there appears to have been a pattern of progressive molecular development from C27 alcohols to C27 acids to C24 acids. The main components in human bile are the C24 compounds chenodeoxycholic (45%), deoxycholic and cholic acids (31%), with hydroxyl groups of the 3α,7α-, 3α,12α- and 3α,7α,12α-configurations, respectively. In contrast, bile in mice contains mainly the more hydrophilic muricholic (hydroxylated at the 6β position) and cholic acids, so experimental data from laboratory animals cannot always be extrapolated to humans. Apart from other primates, only hamster bile is similar in composition to that of humans.
The three classes of bile acids and alcohols can be considered in terms of ‘default’ structures with hydroxylation of the tetracyclic ring nucleus, i.e., with hydroxyl groups at C-3 (epimerized from the 3β-hydroxyl group of cholesterol) and at C-7, together with either a primary alcohol or a carboxyl group at the terminal carbon atom of the side chain. Further substituents can then be added to the default structures, either on the nucleus or the side chain or on both.
Bile alcohols and acids exhibit great structural diversity among animal species. For example, structural variation occurs in the stereochemistry of the A/B ring juncture in the steroid nucleus, in the sites of hydroxyl or keto groups, and in the orientation of hydroxyl groups, i.e., whether they are α or β to the ring. The length of the side chain can vary, while hydroxyl groups of variable orientation and double bonds may be present or absent. In addition, the stereochemistry of the C‑25 carbon atom and the site of the carboxyl group can differ. As of the last count, 25 different bile alcohols with three to six hydroxyl and/or keto groups are known, together with 45 C27 and 40 C24 bile acids, but novel structures continue to be reported. The differing structures can be interpreted in terms of evolutionary relationships between species and families. For example, a 7β-hydroxyl group is found in ursodeoxycholic acid primarily in bears, i.e., it is an epimer of chenodeoxycholic acid with very different physicochemical and biological properties. Hyocholic acid with 3α,6α,7α-hydroxyls is a major component of pig bile.
The transformation to a cis-fused configuration at the A/B ring junction as illustrated accentuates the change in polarity of the molecule, creating hydrophilic (α) and hydrophobic (β) faces, with the hydrophilic hydroxyl groups oriented towards the α-face (concave or lower side), while the hydrophobic methyl groups are oriented towards the β-face (convex or upper side). Bile acids are thus amphipathic molecules with powerful detergent properties.
Allo-bile acids in lower vertebrates are flat because of an A/B trans-fusion (5α-stereochemistry). A few planar bile acids retain the cis-conformation at the A/B ring junction, either because of an alpha arrangement of the C5 hydrogen atom as opposed to the usual beta arrangement or there is a double bond involving carbon 5. The most common of these are allo-cholic acid, 7α,12α-dihydroxy-3-oxochol-4-en-24-oic acid, 7α-hydroxy-3-oxochol-4-en-24-oic acid and 12α-hydroxy-3-oxochol-4,6-dien-24-oic acid. Other than certain disease states, they are only found in the healthy human fetus and newborn and in pregnant women, but not in healthy adults.
Bile acid conjugates: A further complication is that much of the bile acids are secreted into bile in the form of conjugates with the carboxyl group and the amino acids taurine and to a lesser extent glycine. Taurine conjugation is the rule in fish, amphibians, reptiles and birds, and it also occurs to some extent in mammals such mice, rats and dogs; C27 bile acids are conjugated exclusively with taurine. There are substantial species differences in the nature of the conjugation, but glycine conjugation is typical in herbivores and primates, including humans, although other forms of conjugation occur to a lesser extent, e.g. with glucose or by sulfation, or with N‑acetylglucosamine at C7. Conjugation in this manner lowers the pKa of bile acids. Although the amount of sulfated bile acids in serum and bile tends to be small, they constitute a high proportion (~70%) of those in urine, and this is an important route for detoxification and elimination from the body in humans. Bile alcohols conjugated with sulfate have a pKa similar to that of taurine conjugates.
The physical properties of bile acid conjugates are obviously the key to their function. Relative to most sterols, the additions increase substantially the acidity of the molecules and their solubility in water. At the physiological pH values in the intestines, the bile conjugates ionize and exist in salt form. In this conjugated state, the molecules cannot enter the epithelial cells of the biliary tract and small intestines. Their amphipathic nature enables them to form mixed micelles with phosphatidylcholine in solution, and these micelles are relatively stable in the presence of calcium ions.
2. Biosynthesis and Metabolism of Bile Acids
Although there are a number of different biosynthetic routes to bile acids from cholesterol, there are four main steps, and the liver is the only organ concerned in the production of the ‘primary’ bile acids. In fact, there are at least 16 enzymes that catalyse up to 17 reactions to convert insoluble cholesterol into a highly soluble conjugated bile salt. At least one transporter and multiple cellular compartments, which includes the cytosol, endoplasmic reticulum, mitochondria, and peroxisomes, are also involved. What has been termed the ‘classical or neutral’ pathways to the biosynthesis of the ‘root’ bile acid, chenodeoxycholic acid, is believed to be the main mechanism in humans under normal physiological conditions and occurs exclusively in hepatocytes. These produce the primary bile acids, while secondary bile acids are formed by microbial action in the intestines as discussed in the next section.
In brief, the first step is rate limiting and involves the synthesis of 7α-hydroxy-cholesterol by a cholesterol 7α-hydroxylase (CYP7A1) in the endoplasmic reticulum, as described in our web page on oxysterols. In the next step, epimerization of the 3β-hydroxyl group is effected by a specific oxidoreductase, before the double bond in position 5 is hydrogenated by one of two reductases in step 3. In the last series of reactions, the side-chain is oxidized in the mitochondria and the resulting 3α,7α‑dihydroxy-5β-cholestanoic acid is converted to the CoA ester in the endoplasmic reticulum for transport into the peroxisomes where the side-chain is cleaved by the same enzyme that produces 27-hydroxycholesterol, i.e., sterol-27-hydroxylase (CYP27) (see also our web page on oxidized sterols), to remove the three terminal carbons and eventually produce chenodeoxycholic acid.
Synthesis of chenodeoxycholic and cholic acids occurs by a similar route up to a branch point where a sterol 12α-hydroxylase (CYP8B1 - another of the cytochrome P450 family) introduces a 12‑hydroxyl group into the steroidal side-chain en route to the latter. The eventual result is that cholic and chenodeoxycholic acids are produced in approximately equal amounts. In mice, the formation of muricholates is catalysed by CYP2c70.
An alternative lesser pathway for the synthesis of bile acids is now known to exist that utilizes other oxysterols, catalysed by sterol 27-, 25- and 24-sterol hydroxylases, for example, as the precursors(see our web page on oxysterols). It is often termed the 'acidic pathway' as acidic intermediates are formed when the oxidation of the side-chain of cholesterol precedes the modification of the steroid ring. Oxysterol 7α-hydroxylases are the key enzymes in this second pathway, illustrated for 27‑hydroxycholesterol. In this instance, bile acid synthesis is initiated in the inner membrane of mitochondria by sterol 27-hydroxylase, but the rate limiting step may be cholesterol transport into the mitochondria of hepatocytes, but also at some extrahepatic sites, including macrophages and endothelial cells. The process continues in the endoplasmic reticulum and the cytoplasm, to produce chenodeoxycholic acid. At each step, specific transport mechanisms are required that are not fully understood. This biosynthetic pathway is believed to produce less than 30% of the bile acids in humans, but the various intermediates have important signalling functions. It has been suggested that this is their primary function and that bile acid production may have been an added bonus during evolution.
The presence of planar bile acids in the human fetus and infant may be reflective of less evolved biosynthetic pathways. In patients with the genetic disorder Smith-Lemli-Opitz syndrome, a defect in cholesterol biosynthesis leads to elevated levels of 7-dehydrocholesterol in plasma, and thence to a third pathway that proceeds through 7-oxo and 7β-hydroxy intermediates, so avoiding cholesterol, and results in the formation of unusual Δ5‑unsaturated bile acids. There is concern that in pregnant patients with this condition, some of these intermediates have been detected in amniotic fluid, and they have the potential to interfere with the function of hedgehog proteins, which are critical to developmental processes in the infant. This pathway occurs also in healthy humans but to a minor extent.
Finally, before secretion into bile, a high proportion of the bile acids produced by both routes are converted in the peroxisomes to conjugates with the amino acids taurine, a sulfonic acid-containing compound derived from cysteine (see our web page on sulfonolipids), and/or glycine by N-acylamidation by means of a bile acid:CoA synthase and a bile acid:amino acid transferase. In humans, the ratio of glycine to taurine conjugation is about 3 to 1, while in rodents >95% of bile acids are conjugated with taurine.
Regulation of bile acid synthesis involves complex processes, which are linked to the metabolism of cholesterol, retinoids and fatty acids. However, the main control is exerted via the rate-limiting enzyme cholesterol 7α-hydroxylase, the activity of which can be modified by a number of different pathways, but especially by the action of bile acids and cholesterol on gene transcription via specific receptors (see below).
Enterohepatic circulation and metabolism: Bile acids are stored in the gallbladder and are cycled between the intestines and liver via the enterohepatic circulation, a highly integrated process that enables conservation and recycling of bile acids to maintain a pool for efficient nutrient absorption and for stability in the intestinal microbiota. Conjugated bile acids are secreted into the canalicular space between hepatocytes bound to a specific binding protein, and they cross the canalicular membrane in an ATP-dependent fashion by a bile salt export pump to enter the bile in the gall bladder (together with phospholipids and cholesterol), where the concentration of bile acids in bile is 100 to 1000 times higher than that in the hepatocytes; this transport against the concentration gradient controls the overall rate of bile acid production. Thence after ingestion of a meal and in response to the gut hormone cholecystokinin, the gallbladder is stimulated to contract with relaxation of the sphincter of Oddi, and results in the expulsion of bile through bile ducts into the duodenum of the small intestine, where they assist the emulsification, hydrolysis and absorption of the partially hydrolysed lipids from the diet (see our web page on triacylglycerol metabolism and below).
Microflora in the small intestine de-conjugate a proportion of the bile acids by means of a bile salt hydrolase, which acts upon a wide range of bile acid conjugates including the six main components of human bile, and catalyses the hydrolysis of amide bonds to form the free bile (and amino) acids, a process that continues to near completion in the large bowel. Some of these bile acids can be absorbed in the intestines, but some is excreted because deconjugation of bile salts increases their pKa to ~5, making them less soluble and less efficiently reabsorbed. On the other hand, intestinal microorganisms in humans can form conjugates of cholic acid with phenylalanine, leucine, and tyrosine, i.e., distinct from those formed within tissues.
Further microbial enzymes can modify the steroidal structures by dehydroxylation, oxidation of 3-, 7- or 12-hydroxyl groups to oxo groups and epimerization to generate secondary bile acids. For example, they act upon the deconjugated bile acids to produce lithocholic from chenodeoxycholic acid and deoxycholic from cholic acid by removing the 7-hydroxyl group (i.e., resulting in 7-deoxy bile acids). These secondary bile acids are cytotoxic, but they can be detoxified in humans by sulfation and/or glucuronidation, or by oxido-reduction, epimerization and side-chain desaturation, to produce many different modified bile acids including hyocholic and ursodeoxycholic acids; the latter has a 7β-hydroxyl group and is produced by epimerization of chenocholic acid (7α-hydroxyl). Epimerization at the C3 hydroxyl group during transit through the intestine is reversed upon reabsorption and recirculation to the liver. More than 50 different secondary bile acids derived from microorganisms have been detected in human feces.
The nature of the conjugates requires membrane transporters for cellular uptake and secretion. In hepatocytes, bile acids sustain canalicular bile flow with the aid of a specific export pump (BSEP), one of a subfamily of ABC transporters, located in the canalicular membrane. This transporter regulates the excretion of bile acids in the aqueous phase into the canalicular space and thence into the intestines, and it is involved in the feedback mechanism for bile acid synthesis.
Once their main task in assisting the digestion of dietary lipids is completed, much of the non-conjugated bile acids are reabsorbed passively throughout the small and large intestines. The more abundant conjugated bile acids require an apical sodium-dependent bile acid transporter in the terminal ileum to cross the brush border membrane of the enterocytes, before they are assisted across the enterocyte by a heterodimer of two proteins, termed organic solute transporter (OST) alpha and beta, which are responsible for driving bile acids through the basolateral membranes and into the venous blood. They are returned to the liver bound to albumin in the portal blood stream, where they are absorbed by the sodium/taurocholate co-transporting polypeptide to complete the cycle. The process is continued by the apical bile salt export pump, which transports the bile salts out of the hepatocyte into primary bile against a steep concentration gradient to merge with newly synthesised bile acids in the gallbladder. In humans, a conjugated bile salt may complete this cycle from two to six times each day. The average pool of bile acids is roughly 2 g, and because of recycling, hepatic secretion into the duodenum is about 12g/day. Similarly, only a little of the secondary bile acids is absorbed into tissues, but these can accumulate slowly as the human liver is unable to convert deoxycholic acid back to cholic acid. The small proportion of bile acids that avoids hepatic extraction and enters the systemic and portal circulation is dynamic both in amount and molecular species composition, and it follows a meal-dependent and circadian rhythm, which has an appreciable influence upon bile acid receptor activation.
Efficient enterohepatic cycling ensures that a relatively constant supply of bile acids is available to facilitate lipid digestion and absorption whenever food is ingested. Each stage of the this process, from synthesis in the liver to intestinal reabsorption to re-uptake by hepatocytes, is closely regulated by complex signalling pathways between the liver and intestines, with bile acids per se having a key function through their actions on the farnesoid X receptor (FXR) expressed in hepatocytes and epithelial cells lining the intestinal lumen (see below).
In adult humans, roughly 0.5g of cholesterol is utilized for bile acid production each day. It has become evident that the 5% of bile acids that is lost into the faeces represents an important element of the turnover of cholesterol. Indeed, this is the major pathway for the removal of cholesterol from the body, and it is important for the maintenance of cholesterol homeostasis both from quantitative and regulatory standpoints.
3. The Functions of Bile Acids
Digestion: As discussed above and in our web page on triacylglycerol metabolism, a major function of bile acids is to act as powerful detergents or emulsifying agents in the intestines to aid the hydrolysis of dietary triacylglycerols and other lipids and the subsequent absorption of unesterified fatty acids, cholesterol, monoacylglycerols, fat-soluble vitamins and other nutrients by the intestinal epithelium. At low concentrations, bile acids are present in a monomeric form, but as their concentration increases, they reach a 'critical micellar concentration' and together with phospholipids they are able to solubilize triacylglycerols and other non-polar lipids in their hydrophobic core. Such mixed micelles have a diameter up to 30 Å, increasing the surface area, enabling interaction of their lipid contents with lipases and enhancing absorption at the brush border membrane. By facilitating the binding of pancreatic lipase with its co-lipase, bile acids stimulate lipolysis of triacylglycerols directly. In addition, they may control the growth, digestive capacity and metabolism of the microbial biome in the small intestine, ultimately with consequences for the physiology and biochemistry of the host, including the metabolic syndrome, obesity and heart failure.
Signalling: As well as their function in the absorption of dietary lipids and in cholesterol homeostasis, bile acids act as signalling molecules that orchestrate blood glucose, lipid and energy metabolism. In common with most biological mediators, subtle structural differences have dramatic effects upon their biological roles. They function as nutrient signalling hormones by activating several receptors in the nucleus especially the farnesoid X receptor (FXRα), and they also interact with G-protein coupled receptors in the plasma membrane, such as the transmembrane G-protein coupled receptor 5 (TGR5 or GPBAR1) . Thereby, they regulate the expression of many genes involved in sterol, triacylglycerol and carbohydrate metabolism. These receptors have selective affinities for different bile acids, for example chenodeoxycholic acid is the most potent stimulator of FXRα, and they exhibit different patterns of expression corresponding to different signalling functions in tissues. FXR expression is most prevalent in hepatocytes and in the ileum, though it has been found at lower levels in many other tissues including the brain, and bile acids can cross the blood-brain barrier from the circulation. Both FXR and the G protein-coupled bile acid receptor are located at the interface of the host immune system with gut microorganisms, and they are important components of the innate immunity system, such as intestinal and liver macrophages, dendritic cells and natural killer T cells, where bile acids may exert beneficial effects. In addition, there are some promiscuous receptors that accommodate bile acids in a non-exclusive manner, including the pregnane X-receptor (PXR), the sphingosine-1-phosphate receptor 2, the muscarinic receptor and the Vitamin D Receptor (VDR).
However, it should be noted that the results of experiments with mice, which are widely used as models in biochemical studies, must be interpreted with caution, as bile acid compositions and functions differ substantially between humans and mice.
Acting via the FXR receptors (hepatic and intestinal) and various signalling pathways, most bile acids exert a negative feedback regulation on their own synthesis and enterohepatic circulation, mainly through inhibition of both the activity and expression of the key enzyme CYP7A1. In collaboration with insulin, they have an influence on the metabolism of lipids and of glucose. For example, they are involved in the regulation of triacylglycerol biosynthesis and the production of very-low-density lipoproteins (VLDL) in the liver, thereby lowering plasma triacylglycerol levels. Bile acid signalling via the FXR receptor is an important regulator of glucose metabolism, promoting glucose tolerance and insulin sensitivity, and there are suggestions that modification of bile acid metabolism may be a useful pharmacological approach to the treatment of the metabolic syndrome and type 2 diabetes. The FXR receptor also has a major influence on cholesterol metabolism and thence on atherosclerosis, and pharmacological intervention with this receptor may prove to be a useful therapeutic approach to liver and metabolic diseases.
In addition, bile acids are intimately involved in the processes of apoptosis and cell survival, and they influence calcium mobilization, cyclic AMP synthesis and protein kinase C activation via their interactions with receptors. The pregnane X receptor functions as a xenobiotic sensor promotes the transcription of detoxifying enzymes. It is activated by high levels of bile acids to assist the FXR receptor to regulate bile acid synthesis, possibly to prevent liver damage. Similarly, activation of the vitamin D receptor in the intestines induces the cytochrome P450 enzyme CYP3A4 that detoxifies excess bile acids. TGR5 is expressed in many different tissues in addition to the intestines, and the discovery that it was activated by bile acids lead to the realization that these had multiple effects on signalling processes throughout the body, for example by stimulating the production of cAMP and phosphorylation of key enzymes relevant to glucose homeostasis and immune cell regulation with potential impacts upon the control of energy expenditure and on the development of obesity. Conjugated bile acids activate the sphingosine-1-phosphate receptor-2, which in turn leads to the activation of various kinases that impact upon the regulation of glucose metabolism.
Most of the enzymes involved in bile acid synthesis play multiple roles in intermediary metabolism. For example, some are involved in the production of oxysterols, others act on intermediates in hormone biosynthesis, some metabolize very-long-chain fatty acids, such as dietary pristanic acid, and another is utilized in vitamin D synthesis.
Other functions: Bile acids activate G protein-coupled receptors at membrane sites, and TBR5 or GPBAR1 is a regulator of bile acid homeostasis, immune response, energy expenditure, and glucose homeostasis. Similarly, conjugated bile acids activate the sphingosine-1-phosphate receptor type 2 (SIPR2) to trigger signalling pathways with direct effects upon hepatic bile acid, glucose, and lipid metabolism. Bile acids bind with high affinity in a hydrophobic pocket in the phosphodiesterase (phospholipase D) responsible for the hydrolysis of N-acyl phosphatidylethanolamine to generate the endocannabinoid anandamide. They stabilize the enzyme to enhance dimer assembly and enable catalysis.
Bile acids and disease: Inefficient biosynthesis and metabolism of bile acids can cause health problems from the neonatal period to adulthood with diverse clinical symptoms ranging from cholestatic liver disease to neuropsychiatric symptoms and spastic paraplegias. Twenty different bile acids have been detected in brain, where they affect the function of neurotransmitter receptors, such as the muscarinic acetylcholine receptor and γ-aminobutyric acid receptor; they are believed to influence neurological disorders such as Alzheimer's, Parkinson's and Huntington's diseases. They are discussed briefly in relation to the metabolic syndrome and insulin resistance above.
At high concentrations, bile acids are toxic and their presence is relevant to the pathogenesis of cancer of the biliary tract and colon, and to inflammatory bowel disease. The planar bile acids tend to be present in higher concentrations also during liver injury and diseases such as cirrhosis. Disruption of intestinal bile acid absorption results in bile acid accumulation in the colon, leading to watery diarrhea and bile acid loss in the stool (bile acid diarrhea syndrome or BAD).
In contrast, the hydrophilic secondary bile acid ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholan-24-oic acid) and its taurine conjugate are used therapeutically for cholesterol gallstone dissolution and in the treatment of primary biliary cirrhosis by stimulating bile flow from the liver. They regulate cholesterol levels by breaking up micelles containing cholesterol in the intestine so reducing the rate of absorption. Also, this bile acid has inhibitory effects upon apoptosis in epithelial cells and is being studied for potential beneficial effects in a number of disease states where apoptosis is deregulated. Ursodeoxycholic acid is believed to be chemopreventative against cancer by inducing inhibition of proliferation and apoptotic and/or autophagic death of cancer cells (the opposite of its effects in epithelial cells), although deoxycholic acid in contrast is tumor promoting. In addition, it has been found to be beneficial in improving peripheral blood flow in chronic heart failure patients and in protecting the heart against reperfusion injury.
Mice deficient in the Bile Salt Export Pump (Bsep), the primary bile acid transporter in liver cells, produce high levels of tetrahydroxy-bile acids such as 3α,6α,7α,12α-tetrahydroxy-5β-cholan-24-oic acid from muricholic acid, and avoid severe liver damage. Bile acids of this type may have potential in the treatment of cholestatic disease in humans. On the other hand, secondary bile acids such as deoxycholate and lithocholate can be cytotoxic molecules leading to oxidative stress, membrane damage, and colonic carcinogenesis in the host.
For many years, gas chromatography linked to mass spectrometry was the method of choice for the analysis of de-conjugated bile acids, and it is still invaluable because of the structural information that can be obtained by electron-impact ionization. However, high-performance liquid chromatography linked to mass spectrometry with electrospray ionization now affords much greater sensitivity when this is required, and this technique is suitable for the analysis of both conjugated and non-conjugated bile acids.
- Baiocchi, L., Zhou, T.H., Liangpunsakul, S., Lenci, I., Santopaolo, F., Meng, F.Y., Kennedy, L., Glaser, S., Francis, H. and Alpini, G. Dual role of bile acids on the biliary epithelium: friend or foe? Int. J. Mol. Sci., 20, 1869 (2019); DOI.
- Dawson, P.A. and Karpen, S.J. Intestinal transport and metabolism of bile acids. J. Lipid Res., 56, 1085-1099 (2015); DOI.
- Donkers, J.M., Abbing, R.L.P.R. and van de Graaf, S.F.J. Developments in bile salt based therapies: A critical overview. Biochem. Pharm., 161, 1-13 (2019); DOI.
- Dutta, M., Cai, J.W., Gui, W. and Patterson, A.D. A review of analytical platforms for accurate bile acid measurement. Anal. Bioanal. Chem., 411, 4541-4549 (2019); DOI.
- Fiorucci, S., Distrutti, E., Carino, A., Zampella, A. and Biagioli, M. Bile acids and their receptors in metabolic disorders. Prog. Lipid Res., 82, 101094 (2021); DOI.
- Guzior, D.V. and Quinn, R.A. Review: microbial transformations of human bile acids. Microbiome, 9, 140 (2021); DOI.
- Hanafi, N.I., Mohamed, A.S., Kadir, S.H.S.A. and Othman, M.H.D. Overview of bile acids signaling and perspective on the signal of ursodeoxycholic acid, the most hydrophilic bile acid, in the heart. Biomolecules, 8, 159 (2018); DOI.
- Hegyi, P., Maleth, J., Walters, J.R., Hofmann, A.F. and Keely, S.J. Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease. Physiol. Rev., 98, 1983-2023 (2018); DOI.
- Hofmann, A.F. and Hagey, L.R. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J. Lipid Res., 55, 1553-1595 (2014); DOI.
- Kiriyama, Y. and Nochi, H. The biosynthesis, signaling, and neurological functions of bile acids. Biomolecules, 9, 232 (2019); DOI.
- Li, J.N. and Dawson, P.A. Animal models to study bile acid metabolism. Biochim. Biophys. Acta, Mol. Basis. Dis., 1865, 895-911 (2019); DOI.
- Macierzanka, A., Torcello-Gómez, A., Jungnickel, C. and Maldonado-Valderrama, J. Bile salts in digestion and transport of lipids. Adv. Colloid Interface Sci., 274, 102045 (2019); DOI.
- Molinaro, A., Wahlstrom, A. and Marschall, H.U. Role of bile acids in metabolic control. Trends Endocrinol. Metab., 29, 31-41 (2018); DOI.
- Shiffka, S.J., Kane, M.A. and Swam, P.W. Planar bile acids in health and disease. Biochim. Biophys. Acta, Biomembranes, 1859, 2269-2276 (2017); DOI.
- Ticho, A.L., Malhotra, P., Dudeja, P.K., Gill, R.K. and Alrefai, W.A. Intestinal absorption of bile acids in health and disease. Comprehensive Physiol., 10, 21-56 (2020); DOI.
- Vaz, F.M. and Ferdinandusse, S. Bile acid analysis in human disorders of bile acid biosynthesis. Mol. Aspects Med., 56, 10-24 (2017); DOI.
- Winston, J.A. and Theriot, C.M. Diversification of host bile acids by members of the gut microbiota. Gut Microbes, 11, 158-171 (2020); DOI.
- Xie, C., Huang, W.K., Young, R.L., Jones, K.L., Horowitz, M., Rayner, C.K. and Wu, T.Z. Role of bile acids in the regulation of food intake, and their dysregulation in metabolic disease. Nutrients, 13, 1104 (2021); DOI.
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