Liver Bile Salts - Stanford Medicine

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Transcript Liver Bile Salts - Stanford Medicine

Anson Lowe
October 2, 2015
Understand the physiologic function of bile salts
The determinants and regulation of bile salts synthesis
Enterohepatic recycling
Bile salts; enterohepatic recycling; cholesterol
Liver Functions
• Bilirubin metabolism
• Protein Synthesis
– Albumin
– Coagulation factors (II, V, VII, IX, X)
Bile Salt Metabolism
Lipid Metabolism
Glycogen storage and gluconeogenesis
Drug metabolism/Xenobiotic transformation
Bile Salts
Phosphatidyl Choline
Bile pigments, protein,
inorganic ions
Bile Salt Function
Lipid digestion and absorption
 Essential for the absorption of cholesterol and
the fat soluble vitamins; A, D, E, and K.
 Major route for cholesterol degradation
 Influences cholesterol synthesis and
Bile Salts
Synthesized in the liver and excreted into the
biliary system
 Stored in the gallbladder
 Participate in lipid digestion and absorption in
the intestine.
 Recycled through absorption in the terminal
ileum and transport back to the liver
Undergraduate Teaching Project ©AGA, Unit 27, slide 54, produced by Milner-Fenwick, Timonium, MD.
Bile Salt Synthesis
Cholesterol is the starting material
◦ hydrophobic
Through a series of hydroxylation steps,
cholesterol is turned into either cholic acid or
chenodeoxycholic acid
Classical Pathway
CYP7A1 - this enzyme marks the entry point
into the classical pathway.
◦ Hydroxylates the 7a carbon of cholesterol
◦ Expressed only in the liver
◦ Can be regulated
 Negative feedback based on bile salt concentration
CYP7A1 Regulation
FXR - a transcription factor characterized by a
DNA binding domain and a ligand binding
domain that binds chenodeoxycholic and cholic
CYP7A1 Regulation
Bile salts will bind to FXR, which promotes an
association with other transcription factors and
results in negative feedback on CYP7A1.
◦ Thus the negative feedback on CYP7A1 inhibits
cholesterol breakdown and potentially contributes to
higher levels serum cholesterol and increased
cardiovascular risk.
CYP7A1 Regulation
FXR responds to the the level of oxysterols
(derived from cholesterol).
◦ Reduces CYP7A1 activity
◦ Promotes cholesterol efflux from the enterocyte
CYP7A1 Regulation
Approaches for decreasing cholesterol levels
and cardiovascular risk.
◦ Lowering the bile salt pool size
 Resection of the terminal ileum to reduce bile salt recycling
 Use of bile sequestrants, which bind and removes bile salts
in the feces.
◦ Develop agents that inhibit FXR binding to the
CYP7A1 DNA regulatory domain.
Tu et al. TCB 10:30 (2000)
FXR Regulation
Positively regulates IBABP (also known as
ILLBP) in the enterocyte where bile salts are
absorbed and recycled in the terminal ileum.
CYP7A1 Deficiency
First identified in 2 brothers with a frameshift mutation that disrupts
CYP7A1 expression
◦ Early gallstone disease
◦ Hypercholesterolemia
 Hypothesis: decrease degradation of cholesterol > down regulates LDL receptor > serum
cholesterol levels rise
◦ Hypertriglyceridemia
Fuchs, Am J Physiol (2003) 284:G551
Abdelmalek et al., J Am Acad Dermatol, 46:161 (2002)
Abdelmalek et al., J Am Acad Dermatol, 46:161 (2002)
CYP27A1 Deficiency
Decrease in total bile acid synthesis, but have normal cholesterol levels
 Cerebrotendinous xanthomatosis
Tendon xanthomatosis
Accumulation of cholesterol in all tissues
Progressive neurologic dysfunction
Premature atherosclerosis
Patients respond to administration of chenodeoxycholic acid
◦ ? mechanism
Bile Acid Conjugation
Bile Acid Conjugation
Cholic Acid
Glycocholate Acid
Taurocholate Acid
Bile Acid Conjugation
Bile acid CoA:Amino Acid N-acyltransferase
◦ Conjugation with either glycine or taurine is
mediated by BAAT
Familial Hypercholanemia (FHC)
Mutations in BAAT resulting in high serum bile acid concentrations
◦ Low transport out of the hepatocyte
Fat malabsorption
◦ Coagulation defects because of vitamin K malabsorption
◦ steatorrhea
Itching - deposition of bile acids in the skin
Familial Hypercholanemia (FHC)
◦ Administration of ursodeoxycholic acid
 Source of conjugated bile acids for lipid absorption
 Provides feedback inhibition of bile acid synthesis
Undergraduate Teaching Project ©AGA, Unit 27, slide 54, produced by Milner-Fenwick, Timonium, MD.
Bacterial Affects on Bile Acid
7a dehydroxylation
◦ Chenodeoxycholic acid > lithocholic acid
◦ Cholic acid > deoxycholic acid
Deconjugation > increases hydrophobicity
Bile Acid Absorption
Conjugated bile acids are reabsorbed by
specific uptake mechanisms
 Unconjugated bile acids are passively absorbed
Bile Acid Uptake
Conjugated bile acids are taken up in the
terminal ileum by a specific sodium dependent
transporter, SLC10A2 (IBAT, ileal sodium/bile
salt transporter).
◦ SLC10A2 is specifically expressed in the ileum
Primary Bile Acid Malabsorption (PBAM)
◦ Congenital diarrhea, steatorrhea, reduced plasma
cholesterol levels, loss of enterohepatic recirculation
of bile acids
Mutations in SLC10A2
Primary Bile Acid Malabsorption - SLC10A2
Oelkers et al., J Clin Invest.,(1997) 99:1880
Ileal Lipid-Binding Protein
Also known as IBABP, ILLBP, ILBP.
 Mediates cytoplasmic transport of bile acids
 Specifically expressed in the ileum
 Expression is regulated by FXR, which enhances
bile acid uptake
Wolkoff, A.w. and Cohen, D.E., Am J Physiol 284:G175 (2003)
Undergraduate Teaching Project ©AGA, Unit 27, slide 54, produced by Milner-Fenwick, Timonium, MD.
Trauner et al., NEJM (1998) 339:1217
Bile Salt Export
ATP-dependent transport by the Bile Salt Export Pump (BSEP).
Also called SPGP.
◦ Hepatocyte specific expression
Progressive Familial Intrahepatic Cholestasis, type
2 (PFIC2)
 Autosomal recessive characterized by severe
cholestasis that results in liver failure and death
 Mutations in BSEP were found by positional
Bile Salt: Hepatocyte > Bile Duct > Gallbladder > Duct
Bile Formation
Bile Acids
 Phospholipids
 Cholesterol
 Bilirubin
 Water and bicarbonate
Phospholipid (Lecithin) Secretion
MDR3 - ATP dependent transporter for phospholipids.
Progressive Familial Intrahepatic Cholestasis, type
3 (PFIC3)
Most mutations have resulted in a prematurely
truncated MDR3 protein
 Presents with childhood jaundice, icterus, diarrhea,
 Liver histology: bile duct proliferation and fibrosis, portal
 Therapy: liver transplantation
Intrahepatic Cholestasis of Pregnancy (ICP)
Usually presents in the 3rd trimester with
 Exhibits a higher rate of fetal death
 Maternal cholestasis resolves after delivery
 Patients are heterozygotes for a missense
mutation in MDR3
Cholesterol Secretion
Cholesterol secretion is influenced to an extent by phospholipid
◦ Mice in which only one MDR3 gene was disrupted displayed half the normal
phospholipid secretion but normal cholesterol secretion
◦ Homozygous knockouts had no cholesterol secretion
Recently defined transporters for cholesterol have been discovered and
are likely to play a role
Lecithin = phospholipid
Copyright ©2002 American Society for Clinical Investigation
Feldman: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease, 7th ed.
Undergraduate Teaching Project ©AGA, Unit 27, slide 54, produced by Milner-Fenwick, Timonium, MD.