Bile Metabolism 2023 PDF

BILE METABOLISM Presented by Dr /Shymaa Ahmed Maher Associate professor of Medical Biochemistry and Molecular Biology  List the composition of bile. Mention the functions of bile. Mention the classification of bile acids. Describe the steps of synthesis of bile acids and salts....

BILE METABOLISM Presented by Dr /Shymaa Ahmed Maher Associate professor of Medical Biochemistry and Molecular Biology  List the composition of bile. Mention the functions of bile. Mention the classification of bile acids. Describe the steps of synthesis of bile acids and salts. Discuss the fate of bile salts. Describe regulation of synthesis of bile acids. Case A 75 years old male patient presented to outpatient clinic with history of colicky pain in the right upper part of the abdomen radiated to shoulder and back, and was associated with nausea, vomiting, indigestion and feeling over thirst. Past medical history :revealed elevated cholesterol level for 1 year. Physical examination : Temperature :38 HR:80 b/min RR:25/min BL.P:120/80mmgh Abdominal examination : no abnormal signs. Lipid profile: TAG:200mg/dl T.cholestrol:280mg/dl HDL:32mg/dl LDL:170mg/dl Abdominal US: confirm presence of gall stone (cholelithiasis) The physician advise the patient with some lifestyle modification, and prescribe him the following drugs : Ursodeoxycholic acid (gall stone solubilizer) And set a date for patient follow up to asses the need for surgical intervention And may be the use of Cholestyramine (bile acid sequestrant)  OVERVIEW OF BILE Bile is a bitter-tasting, dark-green to yellowish-brown fluid, produced by the liver, consists of a watery mixture of organic and inorganic compounds Bile aids in the process of digestion of lipids in the small intestine. Bile is stored /concentrated in the gallbladder and upon eating is discharged into duodenum.  COMPOSITION OF BILE Daily secretion: 500-1000 ml Bile PH: 7.8 - 8.6(alkaline) Water (85-95%) Solids(5-10%) Organic Inorganic Bile acids /conjugated salts inorganic salts sodium Bile pigment =bilirubin potassium, Cholesterol calcium, Fatty acids chloride, Phospholipids (lecithin= bicarbonate Phosphatidylcholine Vs. Guyton & Hall (13th ed(  FUNCTIONS OF BILE Bile acids/salts are amphipathic. They are hydrophilic on one side and hydrophobic on the other side. The cholesterol derived portion of bile acid: hydrophobic The amino acid derived portion: hydrophilic The terms hydrophilic and hydrophobic are used to describe molecules or substances based on how they react to water molecules. Hydrophilic: capable of interacting with water through hydrogen bonds Hydrophobic: lacking affinity for water  FUNCTIONS OF BILE Digestion/absorption functions: emulsification of dietary fat and increased access for lipases, which improves lipid breakdown and the absorption of fat- soluble micronutrients. Excretory functions: main mechanism of excreting cholesterol and bilirubin, as well as lipid-soluble xenobiotics. Immune functions: bile contains IgA and IgG Growth stimulus/signaling function: contains various growth promoters and signaling molecules which act as trophic stimuli for enterocytes. As an alkali, it also has the function of neutralizing excess stomach acid before it enters the duodenum  FUNCTIONS OF BILE Digestion/absorption functions: 1) Emulsification of lipid aggregates: Bile acids have detergent action on particles of dietary fat. Emulsification causes fat globules to break down into minute microscopic droplets, diameter around 1–50 μm in humans Emulsification provides a greatly increased surface area for the action of the enzyme pancreatic lipase, which actually digests the triglycerides.  FUNCTIONS OF BILE 2) Solubilization and transport of lipids in an aqueous environment:- Bile acids are able to solubilize lipids by forming micelles. Bile acids and phospholipids tend to aggregate around droplets of lipids to form micelles, with the hydrophobic sides towards the fat and hydrophilic sides facing outwards. The hydrophilic sides are negatively charged, and this charge prevents fat droplets coated with bile from re-aggregating into larger fat particles. Since bile increases the absorption of fats, it is an important part of the absorption of the fat-soluble substances, such as the vitamins A, D, E, and K  Digestion/absorption functions Micelles :are lipid molecules that arrange themselves in a spherical form in aqueous solutions. The formation of a micelle is a response to the amphipathic nature of molecules, meaning that they contain both hydrophilic regions (polar head groups) as well as hydrophobic regions (the long hydrophobic chain)/act as a surfactant facilitate digestion and absorption of dietary lipids, lipid soluble substances.  FUNCTIONS OF BILE Excretory functions: 1) Role of bile acids in cholesterol metabolism: Hepatic synthesis of bile acids accounts for the majority of cholesterol breakdown. About 500mg of cholesterol is converted to bile acids and eliminated in bile everyday. Bile acids with phospholipid solubilize cholesterol in the bile, thereby preventing its precipitation in the gallbladder. and stone formation 2) Excretion for bilirubin: Bile serves also as the route of excretion for bilirubin by glucuronidation. Bile Acids  BILE ACIDS Bile acids are produced by hepatocytes as end products of cholesterol metabolism, by a series of enzymes that result in the formation of bile acid Bile acids are classified as primary and secondary bile acids. Primary bile acids: - They are synthesized by the hepatocyte. - Include:- 1. Chenodeoxycholic acid 2. Cholic acid  BILE ACIDS Cholic acid & chenodeoxycholic acid reach duodenum through bile In the small intestine and colon, they are converted into secondary bile acids by bacterial action: Cholic acid deoxycholic acid Chenodeoxycholic acid lithocholic acid  BILE ACIDS STRUCTURE The bile acids contain 24 carbons, with two or three hydroxyl groups and a side chain that terminates in a carboxyl group The carboxyl group has a pKa of ∼ 6 (pH in duodenum ∼6). Carboxyl group will be protonated in half of the molecules (the bile acids) and deprotonated in the rest (the bile salts). Cholic acid  BILE ACIDS SYNTHESIS The primary bile acids are synthesized in the liver from cholesterol.  BILE ACIDS SYNTHESIS The primary bile acids are Cholic acid (the largest amount): a triol Chenodeoxycholic acid: a diol In Bile acids: Hydroxyl groups are inserted at specific positions on the steroid structure The double bond of the cholesterol B ring is reduced The hydrocarbon chain is shortened by three carbons. A carboxyl group is introduced at the end of the chain.  BILE ACIDS SYNTHESIS Site: liver The rate-limiting step: introduction of a hydroxyl group at carbon 7 of the steroid nucleus by 7-α-hydroxylase It is an SER associated, typical monooxygenase. It requires oxygen, NADPH, and cytochrome P450.(only found in liver) Subsequent hydroxylation steps are also catalyzed by monooxygenases. The pathway of bile acid biosynthesis divides early into one subpathway leading to cholylCoA, characterized by an extra α- OH group on position 12, and another pathway leading to chenodeoxycholyl-CoA 12 α-hydroxylase  BILE ACIDS SYNTHESIS Conjugation Inside the liver, bile acids are conjugated to a molecule of either glycine or taurine (an end product of cysteine metabolism). Cholic acid Bile acids Chenodeoxychoic acid Amide bond Glycocholic acid Glycochenodeoxycholic acid Bile salts Taurochenodeoxycholic acid Taurocholic acid The ratio of glycine to taurine forms in the bile is ∼3/1.  BILE ACIDS SYNTHESIS  Addition of glycine or taurine results in the presence of fully ionized groups at alkaline PH of bile and duodenum: -COOH of glycine & -SO3 of taurine  Hence, its name as bile salts e.g., Sodium or potassium glycocholate. The conjugated, ionized bile salts are more effective detergents than the unconjugated ones because of their enhanced amphipathic nature ▪ Bacterial action on bile salts : Primary bile salts are further metabolized in the intestine by the intestinal bacteria. Bile salts Glyco- or Tauro-cholate -Chenodeoxycholate Intestinal bacteria Glycine Deconjugation Taurine Bile acids Cholic acid Chenodeoxycholic Intestinal bacteria OH 7α-dehydroxylation 2ry Bile acids Deoxycholic acid Lithocholic  ENTEROHEPATIC CIRCULATION Bile salts secreted into the intestine are efficiently reabsorbed (>95%) and reused. In the intestine, they are reabsorbed in the terminal ileum via the apical sodium (Na + )-bile salt cotransporter and returned to the blood via a separate transport system. They are efficiently taken up from the blood by the hepatocytes via an isoform of the cotransporter. (Note: Albumin binds bile salts and transports them through the blood as was seen with FA.)  REGULATION The principal rate-limiting step in the biosynthesis of bile acids is at cholesterol- 7-alpha hydroxylase reaction. Expression of cholesterol-7-alpha hydroxylase is upregulated by cholesterol and downregulated by bile acids. Elevated levels of cholesterol in the liver stimulate the nuclear receptor liver X factor (LXR), which increases the transcription of cholesterol-7-alpha hydroxylase. Elevated levels of bile acids activate another nuclear receptor bile acid receptor (BAR, also known as farnesoid X receptor [FXR]) which downregulates the transcription of cholesterol-7-alpha hydroxylase.  Hormonal Control of Bile Secretion Stimulus: Undigested lipids and partially digested proteins in duodenum Hormone from gut cells: Cholecystokinin (CCK) Responses: 1. Secretion of pancreatic enzymes 2. Bile secretion 3. Slow release of gastric contents Case A 75 years old male patient presented to outpatient clinic with history of colicky pain in the right upper part of the abdomen radiated to shoulder and back, and was associated with nausea, vomiting, indigestion and feeling over thirst. Past medical history :revealed elevated cholesterol level for 1 year. Physical examination : Temperature :38 HR:80 b/min RR:25/min BL.P:120/80mmgh Abdominal examination : no abnormal signs. Lipid profile: TAG:200mg/dl T.cholestrol:280mg/dl HDL:32mg/dl LDL:170mg/dl Abdominal US: confirm presence of gall stone (cholelithiasis) The physician advise the patient with some lifestyle modification, and prescribe him the following drugs : Ursodeoxycholic acid (gall stone solubilizer) And set a date for patient follow up to asses the need for surgical intervention And may be the use of Cholestyramine (bile acid sequestrant)