Individual bile acids affect bile acid signaling differently in mice
Toxicology and Applied Pharmacology, Volume 283, Issue 1, 2015, Pages 57-64
Bile acids (BA) are known to regulate BA synthesis and transport through farnesoid X receptors in the liver (FXR-SHP) and gut (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is unclear. Therefore, mice were given different doses of five BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (CA), at different concentrations in their diet. Oxycholic acid (UDCA) increased the concentration of a BA in the enterohepatic circulation for one week. The mRNAs of the BA synthesis and transport genes were quantified in liver and ileum. In the liver, mRNA of SHP, the prototypical target gene of FXR, was increased in mice given all concentrations of BA. In the ileum, the mRNA of the intestinal FXR target gene Fgf15 was increased by CA and DCA at lower doses and to a greater extent than by CDCA and LCA. CA and DCA decreased the rate-limiting enzyme Cyp7a1 in BA synthesis more than CDCA and LCA. Cyp8b1 is an enzyme that 12-hydroxylates BA and is thus responsible for the synthesis of CA. CA and DCA are reduced more than CDCA and LCA. Surprisingly, neither a decrease in the conjugated BA uptake transporter (Ntcp) nor an increase in the BA efflux transporter (Bsep) was observed upon FXR activation, but an increase in the cholesterol efflux transporter upon FXR activation (Abcg5/Abcg8). In conclusion, CA and DCA are more potent FXR activators than CDCA and LCA when fed to mice and are therefore more potent in reducing expression of rate-limiting genes in BA synthesis Cyp7a1 and 12-hydroxylation of BAs Cyp8b1 increasing the expression of Abcg5/Abcg8 responsible for biliary cholesterol excretion. However, feeding BA did not alter either Ntcp or Bsep mRNA or protein levels, suggesting that BA uptake or efflux at physiological and pharmacological concentrations of BA is not regulated by FXR.
Bile acid analysis in disorders of human bile acid biosynthesis
Molecular Aspects of Medicine, Volume 56, 2017, pages 10–24(Video) Bile Pathways and the Enterohepatic Circulation, Animation
Bile acids facilitate the absorption of lipids in the gut, but are also needed to maintain cholesterol homeostasis, stimulate bile flow, eliminate toxic substances, and regulate energy metabolism by acting as signaling molecules. Bile acid biosynthesis is a complex process that is distributed across many organelles and requires at least 17 enzymes for the synthesis of the two main bile acids, cholic acid and chenodeoxycholic acid, in addition to various metabolite transporters. Bile acid synthesis disorders can occur from neonatal to adulthood and present with a wide range of clinical symptoms ranging from cholestatic liver disease to neuropsychiatric symptoms and spastic paraplegia. This Review describes the different pathways of bile acid synthesis and then summarizes the current knowledge on genetic disorders of bile acid biosynthesis in humans, with a particular focus on diagnostic bile acid analysis using mass spectrometry.
Enterohepatic circulation and drug disposition: components of systemic pharmacokinetics
Drug Discovery Today, Volume 19, Number 3, 2014, pages 326-340(Video) Enterohepatic Circulation of Bile Acids
Drug disposition information is part of systemic pharmacokinetics and becomes essential when a drug exhibits significant effects at disproportionately low blood levels. This condition may be due to an excess of the parent drug and/or its active metabolites in the blood in tissues. A portion of some drugs that are absorbed from the gut into the systemic circulation via the portal vein can return to the gut via the bile duct and sphincter of Oddi—a complementary non-renal elimination pathway known as enterohepatic circulation (EHC). Here we critically review existing methods, techniques, and animal models for determining drug distribution, elimination, and EHC, and collectively characterize 43 drugs that have undergone EHC. EHC may represent an unexplored method of eliminating unwanted substrates from the body. Interdisciplinary analysis drives our efforts to close technology gaps in drug discovery and development.
Exons 14, 15 and 24 of the ABCB11 gene in Egyptian children with normal GGT cholestasis
Arab Journal of Gastroenterology, Vol. 23, no. 1, 2022, pages 15–19
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare genetic disorder caused by mutations in gene 11 of the ATP-binding cassette subfamily B, member 11 (ABCB11) encodes the bile salt export pump (BSEP), which is the main transporter of bile acids from hepatocytes to the lumen of the tubules. Defects in BSEP synthesis and/or function result in decreased bile salt secretion, subsequent accumulation of bile salts in hepatocytes, and hepatocyte damage. The aim of this study was to detect variants in exons 14, 15 and 24ABCB11A putative PFIC2 patient gene in a cohort of Egyptian infants and children with normal γ-glutamyl transpeptidase (GGT) cholestasis.
This observational, case-control study was conducted in 13 children with suspected PFIC2 and 13 healthy subjects as controls. GenotypingABCB11Genes were extracted using DNA, followed by PCR amplification, purification and sequencing analysis of exons 14, 15 and 24.ABCB11Gen.
The study detected two single nucleotide variants, c.1638+32T>C (rs2241340) in exon 14 and c.3084A>G (p.Ala1028=) (rs497692) in exon 24ABCB11Gen. No variant was found in exon 15.
The study revealed two benign variants involving exons 14 and 24ABCB11Gen. Exons 14, 15, and 24 were not hotspots for common mutations in Egyptian PFIC2 patients. Further study of other exonsABCB11The gene is required to confirm the diagnosis of PFIC2.(Video) Anatomy | Enterohepatic Circulation EXPLAINED
Bile Acids, Obesity and Metabolic Syndrome
Best Practice & Research Clinical Gastroenterology, Volume 28, Issue 4, 2014, Pages 573-583
Bile acids are increasingly recognized as key regulators of systemic metabolism. Although bile acids have long played an important and direct role in nutrient absorption, bile acids also serve as signaling molecules. The interaction of bile acids with the nuclear hormone receptor farnesoid X receptor (FXR) and the membrane receptor G protein-coupled bile acid receptor 5 (TGR5) can regulate the secretion of incretin hormones and fibroblast growth factor 19 (FGF19), cholesterol metabolism and total body energy expenditure . Bile acid levels and bile acid distribution are altered in type 2 diabetes and increase after bariatric surgery, associated with weight loss, improved insulin sensitivity, and improved glycemic control. Therefore, modulation of bile acid levels and signaling using bile acid binding resins, TGR5 agonists, and FXR agonists could serve as a powerful therapeutic approach to treat obesity, type 2 diabetes, and other components of the metabolic syndrome in humans.(Video) Enterohepatic circulation | From anatomy to physiology and clinical aspects
The acidic pathway of bile acid synthesis: not just an alternative pathway
Liver Research, Volume 3, Issue 2, 2019, pages 88-98
Over the past two decades, the prevalence of obesity and metabolic syndromes (MS) such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) have increased dramatically. Depending on their chemical and signaling properties, bile acids play an important role in the digestion of nutrients, their absorption, and the redistribution of absorbed lipids throughout the body. Consequently, there is renewed interest in bile acid pathways and the challenge of gaining insight into new therapeutic approaches to this rapidly growing health problem. Of the two main pathways of bile acid synthesis in the liver, the acidic (alternative) pathway plays the most important role in the production and control of the regulatory oxysterols that help control cellular cholesterol and lipid homeostasis. Cholesterol transport by the steroidogenic acute regulator protein (StarD1) to mitochondrial sterol 27-hydroxylase (CYP27A1), followed by 7α-hydroxylation of oxysterol by oxysterol 7α-hydroxylase (CYP7B1), is a key regulator of this signaling step. Recent observations suggest that CYP7B1 is the ultimate regulator of cellular oxysterol levels. This review discusses the acid pathway and its contribution to lipid, cholesterol, carbohydrate, and energy homeostasis. In addition, it is discussed how dysregulation of the acid pathway leads not only to the loss of its ability to control cellular cholesterol and lipid homeostasis, but also to inflammation.
Copyright © 1977 Elsevier B.V. All rights reserved. Published by Elsevier Inc. Issued by Elsevier Ltd. All rights reserved.
Enterohepatic circulation refers to the process whereby a drug or a metastable metabolite thereof in the liver is secreted into the bile, stored in the gall bladder, and subsequently released into the small intestine, where the drug can be reabsorbed back into circulation and subsequently returned to the liver.What is the Enterohepatic pathway of bile acids? ›
The term enterohepatic circulation (EHC) denotes the movement of bile acid molecules from the liver to the small intestine and back to the liver. Bile acids traverse the hepatocyte and are actively secreted into canalicular bile, completing the enterohepatic cycle.What is enterohepatic circulation of bile and gallstones? ›
Bile acids entering into enterohepatic circulating are primary acids synthesized from cholesterol in hepatocyte. They are secreted actively across canalicular membrane and carried in bile to gallbladder, where they are concentrated during digestion.What is enterohepatic circulation and why is it important? ›
Enterohepatic circulation is responsible for the capture of bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver.How is bile acid recycled by the body and absorbed via? ›
Bile acids are synthesized from cholesterol in the liver and secreted into the small intestine where they facilitate absorption of fat-soluble vitamins and cholesterol (1). The majority of bile acids are reabsorbed from the intestine and returned to the liver via the portal venous circulation.What organ is key to the enterohepatic circulation of bile? ›
Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis.What is the principle of enterohepatic recirculation? ›
Enterohepatic recycling (EHR) is a feedback mechanism resulting from the combined roles of the liver and intestine. EHR begins with drug absorption across the intestine into the portal circulation, followed by uptake into the hepatocytes.What is the major consequence of enterohepatic circulation? ›
The enterohepatic circulation leads to reabsorption of certain chemicals from bile back into blood and the liver and thus influences their elimination, yet its influence on PFAS bioaccumulation remains unclear.What are the factors affecting the enterohepatic circulation? ›
Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.Why do bile acids cause diarrhea? ›
It's a common cause of chronic diarrhea. When bile acids aren't properly absorbed in your intestines, they build up, upsetting the chemical balance inside. Excess bile acids trigger your colon to secrete extra water, leading to watery stools.
The bile acid pool is maintained mainly via the enterohepatic circulation and, to a small extent (about 5%), by the hepatic synthesis of bile acids, as long as the daily fecal loss of bile acids do not exceed 20% of the pool.What triggers bile release? ›
Bile is produced in your liver and stored in your gallbladder. Eating a meal that contains even a small amount of fat signals your gallbladder to release bile, which flows through a small tube into the upper part of your small intestine (duodenum).Why do we recycle bile? ›
Bile can be collected using an external drain (biliary drain), and put back into the digestive system, bypassing any narrowing or blockage of the bile ducts. It can then mix with the food you eat, aiding digestion and fat absorption. This process is known as bile recycling.How are bile acids removed from the body? ›
Only ∼5% of bile acids are not reabsorbed and are eliminated in the feces. This small amount of loss is replenished via de novo synthesis of bile acids in the liver (1,2). The size of the bile acid pool is tightly regulated within the liver and intestine to prevent cytotoxic accumulation of bile acids (2).What absorbs excess bile? ›
Bile acids, the major organic solutes in bile, are avidly absorbed in the distal small intestine and returned to the liver for resecretion, resulting in continuous circulation between the liver and the intestine.What happens to bile acids in the intestine? ›
After their synthesis from cholesterol in the hepatocyte, bile acids pass into the small intestine where they promote intestinal absorption of biliary and dietary lipids prior to their return to the liver in the enterohepatic circulation or their excretion in the feces.What causes high bile acids? ›
Bile acid levels are increased in the serum and liver in patients with obstructive jaundice or cholestasis and, perhaps because of their inherent detergent activities, can cause hepatocyte injury. Thus, increased bile acid levels in hepatocytes may account for some of the liver damage in cholestatic liver diseases.What are the long term effects of bile acid malabsorption? ›
Untreated bile salt malabsorption can increase your risk of forming gallstones and kidney stones. Vitamin B12 is another vital nutrient which is absorbed into the body at the end of the small bowel.Does exercise increase bile production? ›
Exercise required to promote changes in bile cholesterol, bile acids and peripheral cell lipids need not be strenuous. It probably acts by promoting the transport of lipids from the peripheral cells into the liver and by increasing hepatic secretion of bile.What drugs are involved in enterohepatic circulation? ›
Drugs. Chloramphenicol, aspirin, paracetamol, diazepam, lorazepam, morphine, metronidazole. Not only drugs but endogenous substrates like bilirubin, steroidal hormones and thyroxine utilize this pathway.
Final Answer: Option (4) Minerals.What are the symptoms of a bile acid deficiency? ›
- Vitamin deficiencies, specifically of fat-soluble vitamins such as A, D, E, and K.
- Jaundice, the classic yellowing of the skin and whites of the eyes.
- Stunted or abnormal growth.
- Loss of liver function.
- Liver failure.
The main treatments for bile acid diarrhoea are a low-fat diet and taking a medicine called a bile acid binder. A low-fat diet helps to reduce the symptoms of bile acid diarrhoea. Medicines that bind to bile acids in your gut (bowel) are usually very effective.What does bile acid diarrhea feel like? ›
Bile acid diarrhoea (BAD), sometimes also known as bile acid malabsorption or bile salt malabsorption (though this is not always the correct terminology), can result in symptoms such as bowel frequency, urgency, nocturnal defecation, excessive flatulence, abdominal pain and incontinence of stool.What is the meaning of Enterohepatic? ›
en·tero·he·pat·ic ˌent-ə-rō-hi-ˈpat-ik. : of or involving the intestine and the liver.What is most abundant in bile? ›
The most prevalent organic solutes in bile in all vertebrates are bile salts. The chemistry of bile salts varies greatly among species. Bile salts are 24 carbon water soluble products of cholesterol metabolism.Does omeprazole stop bile production? ›
In summary, we have confirmed that after long term treatment with omeprazole, patients with gastric ulcer as well as healthy volunteers show increased deconjugation of bile acids and fat malabsorption caused by bacterial overgrowth in the jejunum.What blocks bile production? ›
The most common etiology of biliary obstruction is gallstones causing common bile duct obstruction, which manifests as pain, nausea/vomiting, and jaundice.What foods absorb bile? ›
Therefore, one way to get rid of bile is to eat more foods that are high in fiber. Furthermore, eating fibrous foods that absorb bile can also help lower blood cholesterol levels by preventing the body from reabsorbing bile. Fruits; Vegetable; Cereals such as oatmeal; Nuts and seeds; Legumes such as lentils and beans.What toxins does bile remove? ›
One of the most important and clinically relevant examples of waste elimination via bile is that of bilirubin. Additionally, the mechanisms involved in elimination of bilirubin are similar to those used for elimination of many drugs and toxins.
The gallbladder stores and concentrates bile from the liver. The bile is then released into the first section of the small intestine (the duodenum), where it helps your body to break down and absorb fats from food.What does bile empties into? ›
The common bile duct passes through the pancreas before it empties into the first part of the small intestine (duodenum).What happens to bile acid after gallbladder removal? ›
Gallbladder removal surgery (cholecystectomy) may also be associated with bile reflux. When your gallbladder is removed, your liver is redirected to release bile directly into your small intestine. But when bile isn't stored and concentrated in the gallbladder first, it can overflow into your stomach.How is bile drained from the liver? ›
Biliary drainage is the insertion of a tube into the bile duct. This is most commonly carried out when the bile ducts are blocked. The bile ducts normally allow bile (a green-brown fluid that is produced by the liver to help with the digestion of fats) to drain from the liver to the small intestine (see Figure 1).What does bile in stool look like? ›
Stool color is generally influenced by what you eat as well as by the amount of bile — a yellow-green fluid that digests fats — in your stool. As bile pigments travel through your gastrointestinal tract, they are chemically altered by enzymes, changing the pigments from green to brown.Can bile acid damage the colon? ›
Bile acids promote colon cancer progression. BAs, especially DCA and LCA, are well-known as toxic BAs to colonic cells.Why am I pooping stomach acid? ›
In your colon, bile acids are reabsorbed back into your bloodstream so they can be used again. From time to time, the bile acids aren't reabsorbed properly, leading to BAM. Too much bile acid in your colon can lead to diarrhea and watery stool, which is why BAM is sometimes called bile acid diarrhea.Can bile acids cause liver damage? ›
Bile acids maintain liver metabolic homeostasis and have anti-inflammatory properties under normal physiological conditions. Accumulation of high levels of hydrophobic bile acids in cholestasis causes liver inflammation and injury.What is the pathway of bile acid synthesis? ›
Bile acid synthesis can occur through two pathways: the classic (neutral) pathway or the alternative (acidic) pathway . The classic pathway occurs in the liver, and accounts for approximately 90% of bile acid synthesis.What is the pathway of bile production? ›
The main steps in the formation of bile are the uptake of bile acids and ions from plasma across the basolateral (sinusoidal) membrane, transport through the hepatocyte, and excretion via the canalicular membrane.
The common bile duct passes through the pancreas before it empties into the first part of the small intestine (duodenum). The lower part of the common bile duct joins the pancreatic duct to form a channel called the ampulla of Vater or it may enter the duodenum directly.What is the primary bile acid synthesis pathway? ›
Bile acids are steroid carboxylic acids derived from cholesterol in vertebrates. The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver and conjugated with taurine or glycine before secretion via bile into the intestine.What are the effects of the enterohepatic circulation? ›
The enterohepatic circulation leads to reabsorption of certain chemicals from bile back into blood and the liver and thus influences their elimination, yet its influence on PFAS bioaccumulation remains unclear.How does bile travel to and enter the small intestine? ›
The liver cells secrete the bile into small canals that lead to the common bile duct. From there, a smaller duct branches off and leads to the gallbladder. The common bile duct ends at the small intestine. The bile produced by the liver flows directly into the small intestine during a meal.Where are most bile acids absorbed? ›
Bile acids, the major organic solutes in bile, are avidly absorbed in the distal small intestine and returned to the liver for resecretion, resulting in continuous circulation between the liver and the intestine.Where is bile reabsorbed in the gut? ›
After their synthesis, bile acids undergo an enterohepatic circulation where they are secreted by the liver along with other biliary constituents, pass into the small intestine, are reabsorbed from the intestinal lumen, and are carried back in the portal circulation to the liver for efficient extraction and secretion ...Where is bile synthesized and what are the major functions of bile? ›
Bile is a fluid that is made and released by the liver and stored in the gallbladder. Bile helps with digestion. It breaks down fats into fatty acids, which can be taken into the body by the digestive tract.