Bile Acid Synthesis and Cholesterol Degradation

Synthesis and Enterohepatic Cycling of Bile Acids

• Bile acid synthesis and enterohepatic cycling are fundamental processes in cholesterol metabolism and fat digestion.
• The primary bile acid pool totals 2-3 grams.
• The liver synthesizes 0.2-0.6 grams of bile acids daily, accounting for approximately 50% of daily cholesterol turnover.
• Biliary secretion occurs daily, cycling 2-3 grams of bile acids about 10 times per day.
• The ileum, a part of the small intestine, reabsorbs ~95% of bile acids (BA) via an Na+-dependent bile acid transporter.
• Fecal loss accounts for 0.2-0.6 grams of bile acids lost daily.

Cholesterol Degradation

• The ring structure of cholesterol is not metabolized into CO2 and H2O, so it must be eliminated from the body.
• Cholesterol is eliminated from the body by
  • Conversion to bile acids and bile salts, excreted in feces.
  • Secretion of cholesterol into the bile, transported to intestine for elimination.

Bile Acids and Cholesterol Excretion

• Bile acid synthesis serves as one of the main mechanisms for excreting excess cholesterol.
• Bile acids aid in solubilizing dietary cholesterol, lipids, and fat-soluble vitamins, assisting in their delivery to the liver.

Primary Bile Acids

• The most abundant primary bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%).

Secondary Bile Acids Formation

• Primary bile acids undergo further metabolism in the intestine by intestinal bacteria.
• Intestinal bacteria aids in the production of secondary bile acids.
• Secondary bile acids include deoxycholic acid and lithocholic acid.

Bile Acid Synthesis Regulation

• 7α-hydroxylation of cholesterol represents the first and primary regulatory step in bile acid biosynthesis.
• Cholesterol 7 α-hydroxylase, a microsomal, ER-associated cytochrome P450 (CYP) enzyme found exclusively in the liver, catalyzes the process.
• Cholesterol 7-hydroxylase is down-regulated by bile acids and vitamin C deficiency.

Bile Acid Synthesis Regulation and Control

• Genes encoding enzymes of bile acid synthesis are tightly controlled, coordinating them with changing metabolic conditions.
• Bile acid metabolites are cytotoxic, so their is tightly controlled.

Bile Salts Formation

• Before entering bile, primary bile acids are conjugated with glycine or taurine (an endproduct of cysteine metabolism).
• Conjugation happens in liver peroxisomes.
• In humans, the ratio of glycine to taurine conjugates is usually 3:1.
• In alkaline bile (pH 7.6-8.4), bile acids exist as bile salts

Bile Salts Characteristics

• Bile salts’ detergents are more effective than bile acids due to their amphipathic nature, making them better at emulsifying fats.
• Only conjugated bile salts are found in the bile.
• Conjugated bile acids (bile salts) make up the major solutes in human bile.

Bile Composition

• Mixture of bile salts, phospholipids, and cholesterol, formed in the liver, travels to the gall bladder through the canaliculi to form bile.
• Bile consists of 85% water, 67% bile salts, 22% phospholipids, and 4% cholesterol.
• Bile also contains electrolytes, minerals, minor levels of proteins, bilirubin, and biliverdin pigments.
• Bilirubin and biliverdin give bile its yellow-green or orange hue.

Bile Release

• Following consumption of dietary lipids, enteroendocrine cells in the duodenum secrete cholecystokinin (CCK) into circulation.
• CCK binds to receptors on the gall bladder, which stimulates the contraction of smooth muscle cells in the gall bladder and relaxation of the sphincter of Oddi, resulting in pulsatile bile secretion into the duodenum.

Bile Salt Function

• Bile salt anions feature a hydrophilic side and a hydrophobic side and tend to aggregate around lipid droplets (TAGs and phospholipids) to form micelles.
  • Hydrophobic sides point toward the fat, while hydrophilic sides face outwards.
• The negatively charged hydrophilic sides prevent fat droplets coated from re-aggregating into larger fat particles.

Surface Tension and Bile Salts

• Each water molecule experiences a pull from other water molecules from every direction.
• Water molecules at the surface do not have molecules above them to pull at them.
• Surface water molecules has more pull from the water below than the surface above.
• Uneven force packs the water molecules at the surface more tightly.
• A thin, dense layer of molecules produces surface tension.

Bile Salts and Surface Tension Reduction

• Bile salts decrease the surface tension of water by adsorbing at the surface.
• Hydrophobic portion of bile salts repels water molecules and pushes up to the surface, weakening hydrogen bonds holding water molecules together and breaking the surface tension of water.

Bile Salts in Digestion

• In the duodenum, bile salts, secreted and mixed with food by peristalsis, form lipid droplets or micelles with fats.
• Bile salts (amphipathic) have a hydrophilic and a hydrophobic side and collect fats on the inside.
• Phospholipids (lecithin) work similarly to break down and help absorb fats as well as fat-soluble vitamins A, D, E, and K.
• Anionic charges prevent micelles from aggregating into bigger fat molecules and facilitate lipid digestion with lipases.
• Without bile, dietary fat passes through intestines untouched, which causes fatty stools, or steatorrhea.

Bile Acid Use and Production

• The body uses 15-30 grams of bile acids per day, based on fat intake.
• The liver typically produces about 600 mg bile salts per day, so they are recycled in a process known as enterohepatic circulation.
• This process is very effective since only 3 grams of salt pool needs to make many turns each day.
• Mainly, bile acids are reabsorbed in the terminal ileum via an Na+-bile salt cotransporter.

Bile Acid Circulation and Return

• Most (>95%) bile acids return to the liver through enterohepatic circulation.
• Primary and secondary bile acids are absorbed in the terminal ileum, and 98-99% is returned to the liver via portal circulation.
• Hydrophobic bile acids are transported by albumin in the portal blood.
• Due to the low solubility of lithocholic acid, it is not reabsorbed to a significant extent.
• Feces eliminates a small fraction (less than 3%) of bile salts not absorbed.
• Between 15-30 g of bile salts are secreted from the liver into the duodenum daily.
• Only 0.2-0.6 g ( less than 3%) of bile acids are lost daily in the feces.
• The liver synthesizes 0.2-0.6 g/day of cholesterol to replace lost bile acids.

Bile Acid Sequestrants

• Bile acid sequestrants, like cholestyramine, bind bile acids in the gut, preventing reabsorption and promoting excretion.
• They are used in the treatment of hypercholesterolemia.
  • The removal of bile acids alleviates the inhibition on bile acid synthesis in the liver, diverting cholesterol into that pathway.
• Dietary fiber also binds bile acids and increases their excretion.

Bile Salt Role and Gallstones

• The primary role of bile salts in the gall bladder bile is to solubilize cholesterol.
  • Solubilizing the cholesterol prevents cholesterol crystallization and the formation of cholesterol calculi.
• Gallstones, also known as cholelithiasis, are cholesterol calculi.

Fat, Cholesterol, and Gallbladder Health

• Fat serves as the main trigger for bile release into the duodenum.
  • Diets low in fats can increase the risk for gallstone formation.
• Cholesterol is critical for bile salt synthesis.
  • Insufficient cholesterol intake may negatively impact gall bladder health.

Gallbladder

• The gall bladder stores bile, although patients undergoing cholecystectomy, or gall bladder removal, are still able to digest dietary lipids through direct bile secretion into the duodenum.
• Bile acids were originally identified as being involved in four primary physiologically significant functions:
• Their synthesis and subsequent excretion in the feces offers the only elimination of cholesterol.
• Bile acids and phospholipids will help dissolve cholesterol in the bile which prevents cholesterol from precipitating in the gallbladder.
• Bile acids help with dietary triacylglycerol digestion through the use of emulsifying agents that will act on triacylglyceride which are accessible to pancreatic lipase.
• Facilitates the absorption of fat-soluble vitamins.

Bile Acids as Metabolic Regulators

• Recent findings shows that bile acids are involved with
  • Controlling their own metabolism and transportation via the enterohepatic circulation
  • Regulating lipid metabolism
  • Regulating glucose metabolism
  • Controlling signaling events in liver regeneration
  • Regulating overall energy expenditure