Bile Secretion & Bile Acid Metabolism

Question 1

functions of bile

Answer 1

1. digestion & absorption of fat (bile acids solubilize dietary fats, fat-soluble vitamins, and cholesterol, leading to mixed micelles)
2. excretion (excess cholesterol, endogenous hydrophobic metabolites, exogenous toxins and drug metabolites)
3. gene regulation
4. anti-bacterial action in small bowel lumen

Question 2

bile - overview

Answer 2

*bile is a secretion of the LIVER
*bile is SECRETED continuously, but FLOW into duodenum is intermittent

Question 3

2 phases of bile flow into duodenum

Answer 3

*interdigestive period: increased sphincter of Oddi tone causes bile to divert to the gallbladder where it is concentrated > 10-fold

*during meals: hepatic bile flow increases & the gallbladder contracts, driving bile into duodenum over several hours

Question 4

control of bile secretion

Answer 4

*secretion of bile is under neural, hormonal, and chemical control
1. NEURAL - vagal activity induces weak gallbladder contractions
2. HORMONAL - secretin, CCK, and FGF19 induce secretion of bile and contraction of gallbladder
3. CHEMICAL - hepatocyte uptake & transport of bile acids stimulates bile flow into hepatic bile canaliculi

Question 5

bile acid structure

Answer 5

*bile acids are synthesized from CHOLESTEROL by hydroxylation, chain shortening, and amino acid conjugation
*bile acids are AMPHIPATHIC (hydrophobic & hydrophilic sides)
*above a critical concentration, bile acids self-assemble into MIXED MICELLES (disk-shaped structures)
*mixed micelles SOLUBILIZE hydrophobic molecules
*cholesterol is extremely soluble in micelles compared to water

Question 6

hepatic bile acid synthesis

Answer 6

1. 7-hydroxylation of cholesterol by the rate-limiting enzyme (7 alpha-hydroxylase)
2. hydrocarbon tail shortening
3. 12-hydroxylation by 12-hydroxylase (for cholic acid)
4. conjugation to glycine or taurine (increases aqueous solubility)

Question 7

gut bacteria bile acid metabolism

Answer 7

*gut bacteria modify primary bile acids by 7-dehydroxylation
*deconjugation removes amino acids glycine and taurine
*primary bile acids converted to secondary bile acids (deoxycholic and lithocholic acid)

Question 8

enterohepatic circulation of bile acids

Answer 8

*the gut recycles bile acids
*ileal bile acids transporters (ASBT) reabsorbs by acids with 95% efficiency
*bile acids taken up from portal blood with high efficiency by the hepatocyte transporter NTCP
*bile acids re-secreted into bile by the canalicular transporter BSEP

Question 9

dietary fat absorption by bile acids

Answer 9

*bile acids form mixed micelles with fatty acids
*mixed micelles increase fatty acid aqueous solubility
*mixed micelles increase the rate of lipid diffusion through the unstirred water layer

Question 10

cholesterol homeostasis by bile acids

Answer 10

*biliary secretion is the ONLY effective route for cholesterol excretion
*bile acids and biliary phospholipids solubilize cholesterol in the simple/mixed micelles and vesicles during hepatocyte secretion
* > 50% of total cholesterol excretion is via conversion to bile acids

Question 11

impact of bile acids on gallstones

Answer 11

*bile acids prevent gallstones by:
-solubilizing cholesterol in micelles
-binding calcium to prevent formation of insoluble salts

*disruption of enterohepatic circulation leads to a decreased bile acid pool, leading to too much cholesterol in the bile and therefore gallstones

Question 12

post-surgical bile acid diarrhea

Answer 12

*post-cholecystectomy:
-mild bile acid malabsorption leading to osmotic diarrhea

*post ileal resection:
-moderate to severe bile acid malabsorption leads to a reduced bile acid pool and malabsorption of fat
-mixed osmotic/secretory diarrhea

*treatment: bile acid binders & low fat diet

Question 13

bile acid diarrhea in bacterial overgrowth

Answer 13

*bile acids are a major cause of diarrhea in small bowel bacterial overgrowth (SIBO)
*pathophysiology:
-increased small bowel bacteria deconjugate bile acids
-deconjugated bile acids are not recognized by the ileal transporter (ASBT)
-bile acid malabsorption reduces the BA pool
-reduced BA pool leads to fat malabsorption
-increased flux of both BA and fatty acids into the colon leads to mixed osmotic and secretory diarrhea

Question 14

antimicrobial effects of bile acids

Answer 14

*bile acids inhibit bacterial growth in the intestinal lumen
*proximal intestine: bile acid/fatty acid mixed micelles exert direct bacteriostatic action
*distal intestine: bile acids act as a hormone that induces expression of anti-microbial factors via the nuclear receptor FXR
*reduced intralumenal bile acids may be a risk factor for SIBO

Question 15

chenodeoxycholic acid

Answer 15

Rx for cerebrotendinous xanthomatosis

Question 16

ursodeoxycholic acid (UDCA)

Answer 16

*used to treat PRIMARY BILIARY CHOLANGITIS (PBC)
*gallstone prevention after bariatric surgery
*acute/chronic cholestasis (sclerosing cholangitis, cholestasis of pregnancy, drug-induced cholestasis)

Question 17

bile acid binders - uses

Answer 17

*hypercholesterolemia
*bile acid malabsorption diarrhea
*type II diabetes