Liver Bile Salts - Stanford Medicine

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Transcript Liver Bile Salts - Stanford Medicine

LIVER
BILE SALTS
Anson Lowe
Medicine
October 2, 2015
METHODS IN ENZYMOLOGY, VOL. 400

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)
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Bile Salt Metabolism
Lipid Metabolism
Glycogen storage and gluconeogenesis
Drug metabolism/Xenobiotic transformation
Bile
H20
84%
Bile Salts
11.5%
Phosphatidyl Choline
(lecithin)
Bile pigments, protein,
inorganic ions
3.0%
1.0%
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
degradation

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
acid.
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

◦
◦
◦
◦
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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
pKa
Cholic Acid
5.0
Glycocholate Acid
3.9
Taurocholate Acid
2.0
Bile Acid Conjugation

Bile acid CoA:Amino Acid N-acyltransferase
(BAAT)
◦ 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)
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Treatment
◦ 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
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Deconjugation > increases hydrophobicity
Bile Acid Absorption
Conjugated bile acids are reabsorbed by
specific uptake mechanisms
 Unconjugated bile acids are passively absorbed
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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)
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Features
◦ Congenital diarrhea, steatorrhea, reduced plasma
cholesterol levels, loss of enterohepatic recirculation
of bile acids
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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
cloning
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,
hepatosplenomegaly
 Liver histology: bile duct proliferation and fibrosis, portal
inflammation
 Therapy: liver transplantation
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Intrahepatic Cholestasis of Pregnancy (ICP)
Usually presents in the 3rd trimester with
jaundice
 Exhibits a higher rate of fetal death
 Maternal cholestasis resolves after delivery
 Patients are heterozygotes for a missense
mutation in MDR3
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Cholesterol Secretion

Cholesterol secretion is influenced to an extent by phospholipid
secretion
◦ 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.