Cholesterol and Bile Acid Metabolism Flashcards
The major components of bile include
Bile acids, phospholipids, and cholesterol
Contains bilirubin, electrolytes such as Na+, K+, and HCO3-, and small amounts of proteins
-Also copper
Bile
Bile has two fundamental functions. What are they?
- ) Lipid digestion and absorption
2. ) Excretion of cholesterol and bilirubin
Fatty acids in the duodenum stimulate the release of
CCK
Leads to the contraction of the gall bladder and the relaxation of the sphincter of Oddi to release bile into the duodenum
CCK
Are amphipathic, i.e. they have both hydrophobic and hydrophilic properties
Bile Salts
The hydrophilic parts of bile are the two or three
OH groups and a negative charge
While superficially similar to cholesterol, the additional hydroxyl groups are all
Below the plane of the ring
-methyl groups are above
Hence the amphipathic nature to these compounds, which plays into their role as
Detergents in the digestion process
Bile acids facilitate lipid digestion through emulsification of fat and formation of
Micelles
Transport the digested products of triacylglycerides (monoglycerides and free fatty acids), which are rather insoluble to the brush borders of epithelium for absorption
Bile salt micelles
Plays an essential role in liver homeostasis
Liver
A 27-carbon hydrophobic four-ringed compound that is an essential component of cell and organelle membranes
Cholesterol
Cholesterol is particularly abundant in the CNS in
Myelinated sheaths
Because of its insolubility in water, cholesterol is transported in the plasma as a component of
Lipoproteins
Cholesterol is not transported as free cholesterol but rather as an
Esterified version (i.e. w/ a fatty acid attached)
Cholesterol is the precursor of other important products as well, including the steroid hormones and the
Bile acids
The cardiac pathologies associated with cholesterol stem from the regulation of its abundance in the serum, packaged in
Lipoproteins
A hydrophobic compound and therefore does not exist dissolved in the aqueous environment of blood as a free compound
Cholesterol
The body’s supply of cholesterol, derived from the diet and from de novo synthesis, is always transported in the blood packaged into
Lipoproteins
Most of the cholesterol in a lipoprotein is located where?
Buried in interior in esterified form
Apart from its roles in cell and organelle membranes, cholesterol is the starting substrate in which three principal biosynthetic pathways?
- ) Steroid hormones
- ) Vitamin D
- ) Bile salts
Bile salts help to excrete the end product of heme degredation which is called
-gives feces a dark color
Bilirubin
In humans, the ring structure of cholesterol can not be metabolized to
CO2 and H2O
Synthesis and subsequent excretion of bile acids in the feces represent the only significant mechanism for the elimination of excess
Cholesterol
Once transported to the intestine for elimination, some of the cholesterol is modified to coprostanol and cholestenol by
Gut Bacteria
Together with cholesterol, make up the bulk of neutral fecal sterols
Coprostanol and cholestenol
The only mechanism the body possesses to eliminate cholesterol is via the bile acids in the feces and by secretion of cholesterol into the bile, which transports it to the intestine for
Elimination
The liver synthesizes which two primary bile acids from cholesterol?
- ) Cholic acid
2. ) Chenodeoxycholic acid
When these primary bile acids are secreted into the lumen of the intestine, a portion of each is dehydroxylated by gut bacteria at
C-7
This dehydroxylation creates the two secondary bile acids called
Deoxycholic acid and lithocholic acid
Thus how many bile acids are there?
Four
What is more soluble, primary bile acids or secondary bile acids?
Primary
The initial products of bile-targeted cholesterol metabolism in the liver
The primary bile salts cholic acid and chenodeoxycholic acid
Their synthesis from cholesterol is a multi step process; the rate limiting step being catalyzed by
7a-hydroxylase (CYP7A)
Hydroxylates cholesterol at the 7 position to form the primary bile acids
CYP7A
This enzyme is found only in the liver and it is localized to the ER
CYP7A
When bile acids accumulate, synthesis is reduced by a negative feedback mechanism that decreases the expression of
CYP7A
Induces bile acid synthesis by activating cholesterol 7a-hydroxylase in some but not all species
Cholesterol accumulation
The most abundant bile acids in the human bile are
Chenodeoxycholic acid and cholic acid
The pKa of bile acids is approximately
6
Therefore, in the contents of the intestinal lumen, which normally have a pH of 6, approximately 50% of the molecules are present in the protonated form and 50% are ionized, which form
Bile Salts
The ionized form of bile acids
Bile salts
Before the primary bile acids are secreted into the canalicular lumen they are conjugated via amide linkages of
Glycine or taurine to the rings carboxyl group
This amide linkage produces the primary bile salts
Glycocholic acid and taurocholic acid
Have pKa values that are much lower than the pH of the intestinal lumen, therefore a higher percentage of the molecules is present in the ionized form
Glycocholic acid and taurocholic acid
These modifications help to further enhance their hydrophilicity as well as decrease their
Cytotoxicity
The conjugated bile acids are the major solutes in
Human Bile
During the enterohepatic recycling of bile acids, the structure is altered by bacterial enzymes in the
Distal intestine
First, intestinal bacteria deconjugate the bile salts, removing the
Glycine and Taurine
The 7-hydroxyl group of C7 is also attacked by
Anaerobic bacteria in the colon
The secondary bile acids may be reconjugated in the liver, but they are not
Rehydroxylated
Therefore, more than 95% of the biliary bile acids in healthy humans are
Cholic acid, chenodeoxycholic acid, and deoxycholic acid
Virtually all of the biliary bile acids are in the
Conjugated form
On the other hand, fecal bile acids are almost entirely
Unconjugated
Fecal bile acids consist primarily of the dehydroxylated bile acids
Deoxycholic acid and lithocholic acid
Implies the movement of bile acids from the liver to the small intestine and back to the liver
Enterohepatic circulation
The bile acid pool contains about
2-4g of bile acid
This pool is recycled via the enterohepatic circulation on the order of six to ten times each day, so that how much bile enters the duodenum during a 24 hr. period?
15-30g
Of the total bile salt pool, how much is excreted in feces per day?
0.2-0.6 g per day
Bile acids traverse the hepatocyte and are actively secreted into canalicular bile, completing the
Enterohepatic Cycle
Ileal bile salt transport is highly efficient (about 95%), but approximately 0.2-0.6 g of bile salts escapes the
Enterohepatic cycle each day
This loss of bile acids in the feces represents the body’s sole mechanism for elimination of the four-membered ring originally derived from
Cholesterol
In the liver, bile acids are efficiently transported from portal blood by the
Na+-taurocholate cotransporting polypeptide (NTCP)
These bile salts are then resecreted across the canalicular membrane by the
Bile salt export pump (BSEP)
In the terminal ileum, bile salts are efficiently absorbed in by the
Apical Sodium Bile acid Transporter (ASBT)
In the terminal ileum, they are efficiently absorbed in by the apical sodium bile acid transporter (ASBT) and transported out by the basolateral
-returns bile salts to liver in portal circulation
Heteromeric transporter, OSTα-OSTβ
A small percentage of the bile salts are not reabsorbed and are modified from primary bile acids to secondary bile acids by anaerobic bacteria present in the
Colon
These secondary bile acids are either passively absorbed from the colon or they are
Excreted in feces
Represents one of the most common surgical problems worldwide and is especially prevalent in most western countries
Cholelithiasis (or gallstones)
In the U.S. alone, gallstones are present in 8-20% of the population by the age of 40 and are more likely to develop in women than in men by a ratio of about
2-3:1
What are the three varieties of gallstones?
- ) Cholesterol stones (75%)
- ) Pigmented stones (15-20%)
- ) Mixed
The most common type of gall stone is the
Cholesterol stone
Arise from the crystallization of calcium bilirubinate
Pigmented stones
Increased red blood cell destruction (hemolysis) and abnormal metabolism of hemoglobin (liver disease) cause
Pigmented stones
Tend to form when there is stasis of bile, impaired gallbladder motility, and an imbalance in the bile content
Gallstones
(1) certain genetic factors, including LITH genes,
(2) hepatic hypersecretion of biliary cholesterol,
(3) gallbladder hypomotility,
(4) rapid phase transitions of cholesterol in bile from liquid to solid state, and
(5) certain intestinal factors
Are factors that result in
Cholesterol stones
Certain genetic factors such as LITH genes increase risk for
Cholesterol stones
Normally, a delicate balance exists between the levels of
Bile acids, phospholipids, and cholesterol
When this balance is disrupted, especially when there is supersaturation with cholesterol, there is predisposition for the development of
Cholesterol gallstones
This is because when cholesterol supersaturates, it tends to
Crystallize
In Admirand’s Triangle. The small, blue area is the only area where cholesterol is
Completely soluble
Refers to the blockage of any duct that carries bile from the liver to the gallbladder or from the gallbladder to the small intestine
Bilary obstruction
The clinical setting of cholestasis or failure of biliary flow may be due to biliary obstruction by mechanical means or by metabolic factors in the
Hepatic cells
Common to both obstructive and non obstructive cholestasis is the accumulation of bile pigment within the
Hepatic Parenchyma
Elongated green-brown plugs of bile are visible in dilated bile canaliculi. Rupture of canaliculi leads to extravasation of bile, which is quickly phagocytosed by
Kupffer cells
Droplets of bile pigment also accumulate within hepatocytes, which can take on a fine, foamy appearance, so called
“Feathery degeneration”
Bile deposits as conjugated bile plugs in the
Draining ductules
Bind bile acids in the intestine, resulting in interruption of the reabsorption of bile acids (which is usually 90 percent efficient), thus promoting their excretion
Bile acid sequestrants (BAS or bile acid resins (BAR))
Used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway
BAS and BAR
The available bile acid sequestrants include
Cholestyramine, colestipol, and colesevelam
Certain soluble fibers (psyllium, pectin, wheat dextrin, and oat products) reduce serum levels of
Cholesterol
May interfere with micelle formation in the proximal small intestine, resulting in decreased absorption of cholesterol and fatty acids
Soluble fibers
