Download BioChem pg 635 to 641 ch 34 [4-20

BioChem pg 635 to 641
Bile acids = relatively hydrophilic.
- Very effective detergents because both polar and non-polar regions
- Introduced into biliary ducts of the liver
– stored and concentrated in the gallbladder
-
Discharged in response to food ingestion
Aid in digestion of intraluminal lipids
-form micelles with them
-thereby increasing the intraluminal lipid’s surface area for interaction with lipases
Free cholesterol also enters the gut lumen from the biliary tract
-
~1000mg/daily
o Which mixes with 300mg of dietary cholesterol to form an intestinal pool.
o ~55% of pool is reabsorbed by enterocytes and enters the blood stream
Low cholesterol diet liver synthesizes 800mg of cholesterol per day.
-
Higher intact of dietary cholesterol suppresses the rate of hepatic cholesterol synthesis
It’s FEEDBACK REPRESSION
IV Synthesis of Bile Salts
A. Conversion of cholesterol to Cholic Acid and Chenocholic Acid
Bile salts are synthesized in the liver from cholesterol
Rxns hydroxylate the steroid nucleus and cleave side chain
In the first and rate-limiting reaction
-An alpha-hydroxyl group is added to carbon 7
-the activity of the 7-alpha-hydroxylase that catalyzes this step is decreased
by
an increase in bile salt concentration.
Subsequent steps
-double bond in B-ring is reduced, and additional hydroxylation may occur
- Two different sets of compounds are produced
- one set has alpha-hydroxyl groups at positions 3,7, and 12
-And produces the cholic acid series of bile salt
-other set has alpha-hydroxyl groups only at position 3, 7,
-produces the chenodeoxycholic acid series
Three carbon fragments attached to the ring structure contains a carboxyl group.
pKa of the bile acid is ~6
Therefore in the contents of the intestinal lumen, pH of 6, ~50 of molecules are present in protonated
form and 50%
are ionized, which form bile salts
B. Conjugation of Bile Salts
-Carboxyl group at end of side chain of the bile salts is activated by rxn which requires ATP and
Coenzyme A.
-The CoA derivatives can react with either glycine or taurine (derived from cysteine)
-> forming amides that are known as conjugated bile salts.
In Glycocholic acid and glycochenodeoxycholic acid, bile acides are conjugated with a glycine
-They have a pKa of about 4
-compared to unconjugated form high concentration of conjugated molecules are
ionized in intestines.
Taurine conjugates, taurocholic and taurochenodeoxycholic acid
-All have pKa of 2.
-therefore compared to glycoconjugates EVEN more molecules of this conjugation are
ionized in gut lumen
C. Fate of Bile Salts
Bile salts (produced in liver)-> secreted into bile-> stored in gallbladder -> released into intestine
during a meal->serve as detergents aiding in digestion of lipids
-Intestonal bacteria deconjugate and dehydroxylate the bile salts, removing the glycine and
taurine residues and the hydroxyl group at position 7
-Secondary bile salts lack hydroxyl group at position 7.
-Deconjugated
and dehydroxylated bile salts are less
soluble and therefore less readily resorbed by lumen. Compared to bile
salts not subjected to bacterial action.
Lithocholic acid (a secondary bile salt)
-has a hydroxyl group at position 3
-least soluble bile salt
-Major fate is excression
-
>95% of bile salts are resorbed in ileum and return to liver (via Enterohepatic circ)
Secondary bile salts may be reconjugated in the liver, but are not rehydroxylated!
Steroid nucleus cannot be degraded in the body, excretion of bile salts serves as
major route for removal of steroid nucleus and THUS cholesterol from body.
D. Transport of cholesterol by the blood lipoproteins
- Hydrophobic and essentially insoluble in water of blood, cholesterol and cholesterol esters,
like triacylglycerols and phospholipids, must be packaged as lipoproteins.
- These macromolecules are water soluble
-
Lipoprotein particle is composed of a core of hydrophobic lipids such as cholesterol esters
and triacylglycerols surrounded by a shell of polar lipids (the phospholipids).
o This allows a hydration shell to form around lipoprotein
o This happens when positive charge of the nitrogen atom of the phospholipid forms
an ionic bond with the negatively charged hydroxyl ion of the environment.
o In addition the shell contains a variety of apoproteins that also increase the water
solubility of the lipoprotein.
o Free cholesterols are distributed through out shell
 Stablilize, but allow it to maintain spherical shape.
- Major carriers of lipids are chylomicrons, VLDL, and HDL
- Metabolism of VLDL leads to IDLs and LDL.
- Metabolism of chylomicrons leads to formation of chylomicron remnants.
- carrier mechanism:
o Lipids leaves tissue of origin ->blood stream
o Transported to tissues ->components are used (synthetic or oxidative process) or
stored
- Apoproteins (“apo” describes protein within shell of particle in its lipid-free form)
o Adds to hydrophilicity and structural abilities of the particle
o Also active certain enzymes required for normal lipoprotein metabolism
o Act as ligands on surface of lipoprotein that target specific receptors on peripheral
tissues that require lipoprotein delivery for their innate cellular function.
o TABLE 34.4
E. The Chylomicrons
- Larges and least dense (rich triacyglycerol content)
- Synthesized from dietary lipids within epithelial cells of small intestine and secreted into
lacteals?->enter blood stream left subclavian vein
- Major apolipoproteins
o apo B48
o apo CII
 activates lipoprotein lipase (LPL) to hydrolyze the chylomicrons
 This leads to the release of free fatty acids derived from core
triacylglycerides of the lipoprotein into these target cells
 Muscles cells then oxidize the fatty acids as fuel
 Adipocytes and mammary cells store as Triacylglycerols (fat) or milk
formation
 Chylomicron remnants now depleted of core triacytlglycerols have lost
apoCII, but have other 2 apo!
o apo E
 receptors on plasma membrane of liver cells bind to apoE on remnants
 allowing them to be endocytosed
F. Very Low Density Lipoprotein
-
If dietary intake of carbohydrates exceeds the immediate fuel demands of liver the excess
carbohydrates is converted to triacylglycerols:
Along with free and esterified cholesterol, phospholipids and major apoprotein apoB100 are
packaged to form nascent VLDL
-
-
-
These particles are secreted from liver into bloodstream
Where they accept apoCII and apoE from circulating HDL particles
o This then forms then forms the mature VLDL particle
The density, side of particle and lipid content of VLDL table 34.3
These particles are then transported from the hepatic veins to capillaries in skeletal and
cardiac muscle and adipose tissue as well as lactating mammary tissues where LPK is
activated by apoCII
Activated enzyme facilitates the hydrolysis of the triacylglycerol in VLDL
o Causing release of fatty acids from glycerol form portion of core triacylglycerols.
o Fatty acids are oxidized as fuel by muscle cells used in resynthesize of
triacylglycerols in fat cells used in milk production in lactating breast.
The residual particles remaining in the bloodstream are called VLDL remnants ~50% are
taken up from blood by liver cells through binding of BLDL apoE to hepatocyte plasma
membrane apoE receptor and endocytosised