Bile Metabolism

Question 1

List the 3 major components of solids dissolved in bile.

Answer 1

Bile is an aqueous solution of bile acids/salts, phospholipids (lecithin) and cholesterol. These compounds comprise 80% of the total solids dissolved in bile.

Question 2

Define the 2 major functions of bile.

Answer 2

1. Emulsify fats and fat soluble vitamins (ADEK), aids in lipid digestion and absorption via amphipathic bile salts
2. Provide a means of excretion for cholesterol and bilirubin (breakdown of Hb)

Question 3

What happens to bile when someone fasts? What happens after a meal?

Answer 3

When fasting, bile is stored in the gallbladder where most of the body’s bile salt pool is found. Post-prandially, CCK promotes the release of bile into the duodenum and the Sphincter of Oddi to relax.

Question 4

Describe the 2 primary bile acids that are derived from cholesterol.

Answer 4

Both of these bile acids have 24 carbons as opposed to 27 in cholesterol and gained a carboxylate group.

1. Cholic acid - has the 12-hydroxyl that Chenocholic acid lacks.
2. Chenocholic acid

Question 5

Bile acids are ______ planar molecules, meaning they are _____ on one side compared to the other.

Answer 5

Amphipathic planar molecules are HYDROPHILIC on one side compared to the other.

Question 6

What enzyme is responsible for catalyzing the RDS in biosynthesis of bile acids from cholesterol? What are it’s allosteric effectors?

Answer 6

7-alpha hydroxylase (CYP7A1) adds a hydroxyl group to C7 @ cholesterol in the RDS for BA biosynthesis. This produces 7-alpha-hydroxycholesterol. Cholesterol stimulates the enzyme whereas cholic acid (product) is the negative allosteric effector.

Question 7

The conjugation of bile acids in the liver with ____ or ____ lowers their pKa. What bile acids do each form, respectively?

Answer 7

Addition of taurine to cholic acid forms taurocholic acid (pka = 2). The addition of glycine makes glycocholic acid (pka = 4)

Question 8

If the pH of the duodenum is 6, what is the status of cholic acid (pKa = 6) in the duodenum?

Answer 8

Neutral (half protonated and half deprotonated)

Question 9

In the duodenum, the primary bile acids are more _____ because their pKa’s are ___ than the pH in the duodenum.

Answer 9

Primary bile salts are more HYDROPHILIC because their pKa’s are LOWER than duodenum’s pH. This makes them better at emulsifying fats.

Question 10

Which are the least soluble in water and most hydrophilic, respectively in the list (cholesterol, cholic acid, chenodeoycholic acid, glycocholic acid)?

Answer 10

Most hydrophobic = Cholesterol;

Most hydrophilic = Glycocholic acid (lowest pKa = more ionizable in water)

Question 11

Describe the process of emulsification by bile acids/salts.

Answer 11

Bile salts with their hydrophobic face stick to clumpy fat globules and pull them apart into smaller pieces that are more digestible for lipases. The forming micelles help with fat absorption.

Question 12

What happens to bile acids in the lumen by the time they reach the terminal ileum?

Answer 12

Up to 95% of the bile acids is reabsorbed from the lumen back into circulation (portal vein) by the time digested food reaches the distal intestines.

Question 13

Since bile is toxic to bacteria in the gut, they all have what enzyme in common? What does this enzyme produce?

Answer 13

Gut bacteria all have the enzyme that is able to dehydroxylate primary bile salts by removal of the hydroxyl group at C7 and “deconjugate” them. This process produces secondary bile salts (deoxycholic acid and lithocholic acid)

Question 14

Rank the following in terms of least soluble to most soluble. (Primary bile acids, cholesterol, secondary bile acids)

Answer 14

Cholesterol (hydrophobic) < Secondary bile acids (lost C7 hydroxyl group) < Primary bile acids

Question 15

When the distal ileum is removed via surgery, there will be an increase in bile acid ____.

Answer 15

Bile salt synthesis by hepatocytes increases.

Question 16

How are the negative effects of ileal resections managed?

Answer 16

By limiting dietary fat intake and supplementing the diet with medium-chain triglycerides and fat-soluble vitamins.

Question 17

Excretion of _____ is the primary mechanism for eliminating cholesterol from the body.

Answer 17

Bile salts.

Question 18

Describe how Bile Acid Sequestrant (i.e. cholestyramine = Questran) can treat a person with high cholesterol levels.

Answer 18

Sequestrants bind bile acids in the intestine. These BAS compounds prevent the reabsorption of bile acids and increase the conversion of cholesterol to bile acids, thus effectively reducing cholesterol levels.

Question 19

What role does Soluble Fiber have on cholesterol levels?

Answer 19

Dietary fiber naturally sequesters bile acids to increase the elimination of cholesterol from the body.

Question 20

Describe the 5 step mechanism to how bile is shuttled between hepatocytes and enterocytes (with transporters).

Answer 20

1. From the portal vein, bile acid is cotransported into liver cell via NTCP.
2. Bile is exported into the biliary canaliculi via BSEP
3. From the apical membrane, bile is coupled to reabsorption with Na+ in distal ileum enterocyte.
4. From the basolateral membrane, bile is effluxed into the portal vein via OST.
5. BA is transported across the basolateral side of the hepatocyte from the hepatic sinusoidal capillaries.

Question 21

A disparity in the balance of dissolved bile solids can result in ______.

Answer 21

Cholesterol-type gallstones from the formation of lithogenic bile, as from the supersaturation of cholesterol.

Question 22

Maximal bacterial transformation of primary bile aids to secondary bile acids occurs in the _____.

Answer 22

Colon, where most of our gut bacteria lie.

Question 23

The least soluble part of bile is ____. The components known for keeping this insoluble part in solution are ____ and ____.

Answer 23

Cholesterol is the least soluble part of bile. Phospholipids and bile salts keep it aqueous in bile solution.

Question 24

The most common type of gallstones are from _____. The second most type of stones form from ____.

Answer 24

Cholelithiasis describes the condition of cholesterol gallstones. The second common form is from precipitation of bilirubin.

Question 25

Name 3 common causes for the formation of cholesterol gallstones.

Answer 25

1. Ileal removal - lower bile salt pool increases incidence of this.
2. High fat/cholesterol diet results in supersaturation of cholesterol.
3. Low levels of Lecithin or bile salts increases cholesterol crystallization

Question 26

Explain how the dysregulation of certain transporters can lead to gallstones.

Answer 26

Lower activity of ABCB4 (phospholipids) and or BSEP (bile acids) can increase the incidence of crystallized cholesterol. The increased activity of ABCG5/G8 for cholesterol can result in the supersaturation of bile too.

Question 27

Define the signs/symptoms associated with a biliary obstruction at the Cystic bile duct.

Answer 27

Painful gallbladder contraction “cholic pain”

Question 28

Define the signs/symptoms associated with a biliary obstruction at the Common bile duct.

Answer 28

No bile release into duodenum = failure to digest fats and JUANDICE (failure to excrete bilirubin)

Question 29

Define the signs/symptoms associated with a biliary obstruction at the Pancreatic duct.

Answer 29

No bile nor pancreatic secretion into duodenum = serious MALNUTRITION or Acute pancreatitis (auto-digestion from activated enzymes)

Question 30

Why are women more likely to develop gallstones than men?

Answer 30

This 2:1 increase in Cholelithiasis in women as compared to mean correlates to the higher estrogen levels in women that is linked with systemic cholesterol.

Question 31

What common signs and symptoms are linked with Cholelithiasis?

Answer 31

Abdominal pain, nausea, Murphy sign (pain on palpitation of right upper quadrant upon inhalation)

Question 32

Why can bile salts be seen in systemic circulation after a LARGE meal?

Answer 32

Postprandial peaks of bile acids can be seen in systemic circulation since small amounts of reabsorbed bile acids from the liver after a meal can escape into the bloodstream.

Question 33

List 4 morphological features of intracellular cholestasis as seen in histological slides.

Answer 33

1. ENLARGED Cholestatic hepatocytes
2. Dilated canalicular spaces with bile pigments (brown bile plugs).
3. Apoptotic cells.
4. Kupffer cells with bile pigments.

Question 34

Why would a patient experiencing cholesterol gallstones, as indicated by RUQ post-prandial pain, be given exogenous chenodeoxycholic acid?

Answer 34

Chenodeoxycholic acid is a MORE POLAR bile salt that increases the solubility of dissolved cholesterol in bile. High % of this as well as phospholipids in bile helps prevent cholesterol crystallization.