Bile acids

Not a single gram of dietary fat can be absorbed by the body without the bile constantly secreted by the liver, the most important organic constituents of which are the steroidal cholic or bile acids.

Functions of bile acids

Bile acids (BAs) are not only key components of bile formation (making up about two-thirds of its organic compounds), but also fulfill several functions at once:

• acting as detergents (surface active substances), provide emulsification of fats (lipids) - breaking them down into tiny particles (micelles) - and thus facilitate their absorption;
• regulate cholesterol metabolism - its elimination from the body and reverse transport;
• are involved in the regulation of the motor function of the gallbladder and GI tract;
• stimulate the pancreas;
• inhibit bacterial growth in the watery contents of the proximal small intestine;
• support the endogenous intestinal microbiota;
• Help eliminate potentially toxic bilirubin, drug metabolites, heavy metals, etc. From the body.

It is in the ability to transform fats insoluble in water into an emulsion by their colloidal dissolution (solubilization) that the role of bile acids in digestion lies, since the micelles formed in this process multiply the surface area, which is affected by digestive enzymes of the pancreas and intestine.

Thus, it is simply impossible to overemphasize the role of bile acids in the digestion and absorption of fats, fatty acids, and fat-soluble vitamins.

Also read - Composition, functions and properties of bile

Composition and types of bile acids

The list of bile acids includes:

• primary bile acids, which include the main LCs - cholic acid and chenodeoxycholic acid;
• secondary bile acids - deoxycholic acid and lithocholic acid, which are 7α-dehydroxylated derivatives of primary LCs;
• tertiary bile acid - ursodeoxycholic acid.

In the bile that accumulates in gallbladder, there are other types or kinds of bile acids that are formed in the liver. These are the so-called paired bile acids: glycocholic and taurocholic, glycodeoxycholic and taurodeoxycholic, glycochenodeoxycholic and taurochenodeoxycholic.

Bile acid molecules have a sterane framework (from a saturated tetracyclic hydrocarbon) and a C24 structure: the steroid core consists of 24 carbon atoms that form steroid rings. So the structure and composition of bile acids - the presence of a side chain with a functional carboxyl (-COOH) or hydroxyl (OH) group in the molecules - allow us to refer them to steroidal mono-basic oxycarboxylic acids.

The most important property of LCs is their diphilicity (amphiphilicity): their molecules have non-polar hydrophilic and polar hydrophobic parts, i.e. They are able to both absorb water and repel it. The most hydrophilic bile acids are represented by ursodeoxycholic acid and chenodeoxycholic acid, and lithocholic LC is the most hydrophobic.

Formation of bile acids

The synthesis of bile acids (cholic acid and chenodeoxycholic acid) occurs in the liver, and the process begins with the formation of 7α-hydroxycholesterol (7α-OHC), a derivative of cholesterol produced by its hydroxylation with the participation of the hepatic enzyme CYP7A1.

Primary bile acids are synthesized from 7α-OHC in the course of hydroxylation reaction by enzymes of cell organelles of hepatocytes, which leads to modification of steroidal cholesterol core. And, according to experts, cholesterol catabolism in the body is carried out mainly due to the constant synthesis of LC by the liver.

The conjugation of bile acids takes place in the liver - their combination with amino acids glycine (75%) and taurine (25%) and formation of paired LCs. As a result, their ability to penetrate the cell membranes of the gallbladder and duodenal mucosa cells is leveled, which allows bile acids to persist in bile in significant concentrations. Besides, conjugation increases emulsifying properties of bile acids.

And the parallel process of deprotonation of surface functional groups in conjugated LC molecules decreases their ionization level (pCa), which increases water solubility and surface sorption properties of bile acids, also promoting lipid emulsification.

Before secretion into the gallbladder through the tubule membranes of hepatocytes, bile acids in the liver osmotically pull other bile components (sodium, water, phospholipids, cholesterol, bilirubin) into the tubules between neighboring hepatocytes.

A number of sources note that bile acid salts similar to bile acids are formed by conjugation of LCs to amino acids, and it is these conjugated bile acids that are often referred to as bile acid salts (using the terms "acids" and "salts" interchangeably).

Dehydroxylation and deconjugation of bile acids (about one third of total volume of cholic and chenodeoxycholic acids) with formation of secondary LCs (deoxycholic and lithocholic) takes place in the lumen of small intestine under the influence of intestinal microbiota. And the formation of tertiary ursodeoxycholic acid is the result of changes in the configuration of primary chenodeoxycholic acid molecules under the influence of intestinal bacterial enzymes.

Liver-intestinal circulation and bile acid metabolism

The metabolism or metabolism of bile acids occurs through a complex biochemical process known as hepatic-intestinal or enterohepatic circulation of bile acids.

Schematically, the continuous circulation of bile acids between the liver and the intestine can be represented as follows: synthesized bile acids are secreted by the liver together with other bile components through the bile ducts; as part of the bile they enter the small intestine (assisting in the digestion and absorption of fats); in the intestine they are reabsorbed into the blood (via the Na+-dependent transport system) and transported to the liver via the portal or portal vein (vena portae); in the liver, bile acids are re-conjugated.

The volume of bile acids does not exceed 3-5 g, and during one day they pass through the intestine up to a dozen times.

Bile acids in the duodenum form mixed micelles with food lipids. Absorption of solubilized dietary fats begins in the proximal and middle intestine, while absorption of bile acids occurs mainly in the distal small intestine - in the ileum. A part of unconjugated bile acids is absorbed and returns to the liver, where they undergo hepatic reconjugation, mix with newly synthesized LCs and enter the bile.

It should be noted that mainly due to enterohepatic circulation the physiological necessary level of bile acids is maintained, and the share of newly synthesized by the liver LCs is only about 5%.

Bile acid levels: where, what kind and why

A condition in which liver cells do not produce bile acids is called acholia. And when bile acids accumulate in the blood, a pathology such as cholemia is defined.

By the way, in serum bile acids the norm is in the range of 2.5-6.8 mmol/L.

Patients take a blood bile acid test or a total bile acid test as part of an evaluation for digestive disorders and if there are problems with the intestines, liver or pancreas - to determine a diagnosis.

What can cause elevated bile acids in the blood?Bile acid levels in the blood are elevated in bile stasis (cholestasis), acute cholecystitis, mechanical jaundice, viral and toxic hepatitis, primary biliary cirrhosis, fatty infiltration of the liver - steatosis, malignant neoplasms of the liver and gallbladder.

Bile acids in pregnancy are often elevated in the third trimester due to intrahepatic bile stasis provoked by high levels of estrogens as well as homones such as secretin and somatotropin.

Decreased bile acids are usually indicative of impaired secretory function of the liver of various etiologies, including those due to genetic defects or side effects of hepatotoxic drugs.

According to gastroenterologists, bile acids in gastric juice may only be present in bile reflux (which can be accompanied by gastric acid throwing into the esophagus) in patients with biliary reflux gastritis and gastroesophageal reflux disease (GERD).

Bile acids may be retained in the small intestine when the large intestine cannot reabsorb them completely. Bile acid malabsorption syndrome (with diarrhea), characteristic of Crohn's disease, gluten intolerance or excessive bacterial growth in the small intestine.

In intestinal dysbiosis there may be an increase in the proportion of unconjugated bile acids due to impaired metabolism, which is also what is manifested by diarrhea.

Normally, bile acids are not detected in the urine. In the early stages of obturation jaundice and in acute pancreatitis small amounts of BCAs appear in the urine. The presence of bile acids in the urine may indicate liver pathologies, including acute and chronic hepatitis and cirrhosis, as well as biliary tract obstruction. In the absence of these causes, the appearance of small amounts of GI in the urine appears to be a consequence of an unsatisfactory state of the intestinal microbiota.

If bile acids are detected in feces, it is explained by the fact that a small amount of bile acids (up to 5%) in interaction with the acidic environment of the large intestine is converted into a solid form and excreted during defecation. And the total excretion of bile acids with feces is balanced by their synthesis in the liver.

Bile acid preparations and to reduce bile acids

Bile acid-lowering drugs belong to the pharmaceutical group of drugs that lower low-density lipoprotein (LDL) cholesterol, particularly in hypercholesterolemia.

The hypocholesterolemic/hypolipidemic drugs Colestyramine or Cholestyramine are an anion-exchange resin and are defined as bile acid sequestrants (from Latin sequestrum - restriction). They are not absorbed after ingestion, but bind to bile acids in the intestine and excrete them with the feces. In this way, GI reabsorption is prevented and hepatic synthesis of bile acids from cholesterol is increased. In addition, bile acid sequestrants have a symptomatic effect in diarrhea.

For the treatment of dyslipidemia, constipation-associated irritable bowel syndrome, as well as functional and chronic constipation, so-called bile acid inhibitors have been developed - specific inhibitors of the Na+-dependent intestinal transport system by which bile acids are reabsorbed. The drug Elobixibat hydrate (Elobixibat), which affects the circulation of bile acids between the liver and the intestine, inhibits the reabsorption of bile acids in the intestine, which increases fluid secretion in the colon and facilitates defecation.

To reduce the absorption of cholesterol in the intestine, dissolve cholesterol gallstones and reduce bile stasis, bile acid preparations containing chenodeoxycholic LC are used: chenofalk, Choludexan, Ursodiol, Ursofalk, Ursosan, Ursolysin, Ukrliv.

Medicines based on components of bile and pancreatin - Festal (Enzistal), Holenzyme and others. - are intended for therapy of diseases with digestive problems. But in digestive disorders, not related to the work of the liver, but due to functional disorders of the pancreas, enzymes that do not contain bile acids are used: Pancreatin, Creon, Penzital, Digestin, Digistal, Panzinorm and others.