Bile Acids and Bile Salts
• Bile consists of a watery mixture of organic and
inorganic compounds. Phosphatidylcholine and
bile salts (conjugated bile acids) are quantitatively
the most important organic components of bile.
• Bile can either pass directly from the liver where
it is synthesized into the duodenum through the
common bile duct, or be stored in the gallbladder
when not immediately needed for digestion.
Structure of the bile acids
• The bile acids contain 24 carbons, with two or three
hydroxyl groups and a side chain that terminates in a
carboxyl group.
• The carboxyl group has a pKa of about six and,
therefore, is not fully ionized at physiologic pH—hence,
the term “bile acid.”
• The bile acids are amphipathic.
• Therefore, the molecules have both a polar and a
nonpolar face, and can act as emulsifying agents in the
intestine, helping prepare dietary triacylglycerol and
other complex lipids for degradation by pancreatic
digestive enzymes
Synthesis of bile acids
• Bile acids are synthesized in the
liver by a multistep,
multiorganelle pathway in which
hydroxyl groups are inserted at
specific positions on the steroid
structure, the double bond of the
cholesterol B ring is reduced, and
the hydrocarbon chain is
shortened by three carbons,
introducing a carboxyl group at
the end of the chain.
• The most common resulting
compounds, cholic acid (a triol)
and chenodeoxycholic acid (a
diol, are called “primary” bile
acids.
Regulation of bile acid synthesis
• The rate-limiting step in bile
acid synthesis is the
introduction of a hydroxyl
group at carbon 7 of the
steroid nucleus by
cholesterol-7-αhydroxylase, an ERassociated cytochrome
P450 (CYP) enzyme found
only in liver.
• The enzyme is downregulated by cholic acid and
up-regulated by cholesterol.
Synthesis of bile salts
• Before the bile acids leave the
liver, they are conjugated to a
molecule of either glycine or
taurine (an endproduct of
cysteine metabolism) by an
amide bond between the
carboxyl group of the bile acid
and the amino group of the
added compound.
• These new structures are
called bile salts and include
glycocholic and
glycochenodeoxycholic acids,
and taurocholic and
taurochenodeoxycholic acids
• The ratio of glycine to taurine forms in the bile is
approximately 3:1.
• Addition of glycine or taurine results in the presence
of a carboxyl group with a lower pKa(from glycine) or a
sulfonate group (from taurine), both of which are fully
ionized (negatively charged) at physiologic pH.
• Bile salts are more effective detergents than bile acids
because of their enhanced amphipathic nature.
• Bile salts provide the only significant mechanism for
cholesterol excretion, both as a metabolic product of
cholesterol and as a solubilizer of cholesterol in bile.
Action of intestinal flora on bile salts
• Bacteria in the intestine
can remove glycine and
taurine from bile salts,
regenerating bile acids.
• They can also convert
some of the primary bile
acids into “secondary”
bile acids by removing a
hydroxyl group, producing
deoxycholic acid from
cholic acid and lithocholic
acid from
chenodeoxycholic acid.
Enterohepatic circulation
• Bile salts secreted into the
intestine are efficiently
reabsorbed (greater than
95%) and reused.
• The mixture of primary and
secondary bile acids and
bile salts is absorbed
primarily in the ileum.
• They are actively
transported from the
intestinal mucosal cells into
the portal blood, and are
efficiently removed by the
liver parenchymal cells.
Enterohepatic circulation
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Bile acids are hydrophobic and
require a carrier in the portal blood.
Albumin carries them in a
noncovalent complex, just as it
transports fatty acids in blood .
The liver converts both primary and
secondary bile acids into bile salts by
conjugation with glycine or taurine,
and secretes them into the bile.
The continuous process of secretion
of bile salts into the bile, their
passage through the duodenum
where some are converted to bile
acids, and their subsequent return to
the liver as a mixture of bile acids and
salts is termed the enterohepatic
circulation .
Bile salt deficiency: cholelithiasis
• The movement of cholesterol from the liver into the bile must
be accompanied by the simultaneous secretion of
phospholipid and bile salts.
• If this dual process is disrupted and more cholesterol enters
the bile than can be solubilized by the bile salts and lecithin
present, the cholesterol may precipitate in the gallbladder,
initiating the occurrence of cholesterol gallstone disease—
cholelithiasis .
Causes of cholelithiasis
• Gross malabsorption of bile acids from the intestine, as
seen in patients with severe ileal disease
• Obstruction of the biliary tract, interrupting the
enterohepatic circulation
• Severe hepatic dysfunction, leading to decreased synthesis
of bile salts, or other abnormalities in bile production
• Excessive feedback suppression of bile acid synthesis as a
result of an accelerated rate of recycling of bile acids.
• Cholelithiasis also may result from increased biliary
cholesterol excretion, as seen with the use of fibrates.
[Fibrates, such as gemfibrozil,3 are used to reduce
triacylglycerol levels in blood].