Download glycocholic acid

Chylomicron
Transport dietary lipids from the intestine to the
peripheral tissues
VLDL – IDL - LDL
• VLDL function: Deliver TG from liver to peripheral tissue cells
• LDL function: Deliver Cholesterol from live to peripheral tissue cells
HDL function:
Reverse-transport cholesterol from peripheral cells to the liver for
excretion
Cholesterol metabolism
Exclusively found in animal: animal sterol
2g/kg for health person
Role of cholesterol
1. An essential component of cell membranes, has a vital role
for membrane functions.
2. Used to synthesize bile acids in the liver.
3. Used to synthesize steroid hormones.
glucocorticoids
mineralocorticoids
androgens
estrogens
progestins
4. Used to synthesize Vitamin D.
Liver is most important organ for cholesterol
metabolism
Cholesterol synthesis
• About 1g of cholesterol is synthesized per day in adults,
liver: 50%; intestine 15%; other tissues: 35%.
• All C-atoms of cholesterol come from acetyl CoA;
reducing equivalents come from NADPH
• Energy to drive synthesis comes from ATP hydrolysis
• Key enzyme (rate limiting enzyme) in cholesterol
synthesis is HMG CoA reductase
Cholesterol synthesis
• First three acetyl CoA forms HMG CoA
• HMG CoA reductase catalyzes the rate
limiting (regulated) step of the pathway,
formation of mevalonic acid from HMG
CoA and 2 NADPH
• Decarboxylation of
mevalonic acid forms
isopentyl-pyrophosphate (IPP,
5-C unit).
• Condensation of two IPP
forms geranyl PP (GPP, 10-C)
• Condensation of GPP and
IPP forms farnesyl PP (FPP,
15-C).
• Condensation of two FPP
forms squalene (30-C).
• Squalene becomes cyclized
lanosterol, and then
cholesterol
Regulation of cholesterol synthesis
• Regulation of cholesterol synthesis via :
– feedback inhibition of HMG CoA reductase by cholesterol
– cholesterol inhibits transcription of HMG CoA reductase gene
– Inhibit by drugs, such as Compactin and Lovastatin.
R= H: compactin
R= CH3: lovastatin
-- hormonal regulation of HMG-CoA reductase
glucagon leads to phosphorylation: inactivate the enzyme
insulin favors dephosphorylation: activate the enzyme
Metabolism of Bile acids
• Formed from cholesterol in
the liver
• Rate limiting step is the
conversion of cholesterol to
7-alpha cholesterol by 7-ahydroxylase
• Utilized during digestion of
fats (act as detergents)
Bile acids & salts
• Before leaving the liver, bile acids are conjugated in amide
linkage to glycine (glycocholic acid) or taurine (e.g.
taurochenodeoxycholic acid)
• These compounds are more fully ionized at neutral pH
(carboxylate and sulfate, with low pKa) and are better
detergents
NADPH + H + NADP
HO
HO
7a-hydroxylase
OH
7a-hydroxycholesterol
cholesterol
12a-hydroxylase
O2; NADPH + H +
2 CoA-SH
O2
NADPH + H +
2 CoA-SH
OH
C
S
CoA
O
C
O
HO
OH
H
cholyl-CoA
HO
OH
H
chenodeoxycholyl- CoA
Synthesis of Bile Acids
S
CoA
Conversion of cholyl-CoA to glycocholic acid

C
S
CoA
O

glycine
CoA-SH
C
CH2 COOH
O

HO
N
H
cholyl-CoA

HO
H
Glycocholic acid
Glycochenodeoxycholic acid
Conversion of cholyl CoA to taurocholic acid
Taurine
Taurocholic acid
Taurochenodeoxycholic acid
Secondary bile acids
• Bacteria in the intestine can remove glycine and taurine
• They can also modify bile acids to form secondary bile
acids (minus one -OH group, e.g., deoxycholic acid,
lithochoic acid)
acid
Glycocholic acid
Deoxycholic acid
Taurocholic acid
Glycochenodeoxycholic acid
Lithocholic acid
Taurochenodeoxycholic acid
About bile acids
• Cholic acid is the bile acid found in the largest amount in
bile
• Cholic acid and chenodeoxycholic acid are referred to as
primary bile acids
• Bile acids are converted to either glycine or taurine
conjugates (in humans the ratio of glycine to taurine
conjugates is 3:1)
• Bacteria in the intestine can remove glycine and taurine.
They can also modify bile acids to form secondary bile
acids (minus one -OH group, e.g., deoxycholic acid,
lithochoic acid).
Function of bile acids
• Aid in digestion and absorption of dietary fat: emulsify fats
due to detergent activity
• Stimulate the action of pancreatic lipase
• Stimulate intestinal motility
• Keep cholesterol in solution (as micelles)
Emulsification of Fat by Bile
• Mixed micelle formed by bile acids, triacylglycerols and
pancreatic lipase
• Detergent character of bile salts is due to the hydrophobichydrophilic nature of the molecules
Bile acids are efficiently recycled
Enterohepatic circulation:
•
Bile acids are efficiently reabsorbed in the intestine and returned via the
portal vein to the liver for reuse (enterohepatic circulation)
•
Of 15-30 g of bile acids secreted/day, only 0.5 g are lost in feces (i.e., 0.5 g of
cholesterol is excreted)
Cholelithiasis
If more cholesterol enters the bile than can be excreted,
cholesterol may precipitate/ crystallize in the gall bladder
leading to gallstone disease
• Causes:
– severe ileal disease
– obstruction of the bile duct
– severe hepatic dysfunction
– excessive suppression of bile
acid synthesis
Lipoproteins and Atherosclerosis
LDL: Risk factor for atherosclerosis
HDL: Protective factor for atherosclerosis
Atherosclerosis
• hardening of the arteries due to the deposition of
atheromas
• caused by the deposition of cholesteryl esters on the
walls of arteries
• atherosclerosis is correlated with high LDL and low
HDL
Author: Sukhinder C. Kaur
572 pages, Springer; $139.00
Cholesterol & risk of heart disease
Total Cholesterol
Category
Less than 200 mg/dL
Desirable level
200-239 mg/dL
Borderline high
240 mg/dL and above
High blood cholesterol (more than doubles risk)
LDL Cholesterol Level
Category
Less than 100 mg/dL
Optimal
100-129 mg/dL
Near or above optimal
130-159 mg/dL
Borderline high
160-189 mg/dL
High
190 mg/dL and above
Very high
HDL Cholesterol Level
Category
Less than 40 mg/dL
A major risk factor for heart disease
40-59 mg/dL
Moderate
60 mg/dL and above
Protective against heart disease
•LDL must be oxidized to be pathogenic (atherogenic)
Lipoproteins and atherosclerosis
1. The endothelium in the arterial wall
becomes more permeable to
lipoprotein and allows migration of
cells to the underlying layer (intima).
2. LDL penetrate the vascular wall and
deposit in the intima, where they
undergoing oxidation to become
oxidized LDL (OxLDL).
3. Oxidized LDL stimulate endothelial
expression of some adhesion
molecules.
4. Adhesion molecules attract
monocytes, which enter the wall and
transform into macrophages.
5. Macrophage take up oxidized LDL, when overload with lipid,
become “foam cells”.
6. Conglomerate of foam cells form fatty streaks or yellow patches
visible in the arterial wall.
7. Dying foam cells release lipid that form lipid pool within the
arterial wall.
Foam cells
8. Surrounding smooth muscle start to secrete a range of small
peptides, which stimulate smooth muscle cells to proliferate and
to migrate toward the lumen side of the arterial wall.
9. In the same time, smooth muscle cells start synthesizing
extracellular matrix, such as collagen.
10. Relocated smooth muscle cells, collagen-rich fibrous tissue,
macrophages all together form a “Cap” that cover the lipid pool.
This is a matured atherosclerotic plaque.
11. The plaque protrudes into the arterial lumen, grows slowly over
years, and finally obstruct the artery. This decreases blood flow in
the affected vessel.
12. Rupture or ulceration of fibrous cap rapidly leads to thrombosis
and obstruct the artery.
Thrombus
Fibrous cap
Lipid core
HDL is Protective
• HDL prevent foam cell formation
• HDL inhibits oxidative modification of LDL
• HDL inhibits expression of adhesion molecules
Improving Your Levels
• Exercise
• Improved diet
• Maintain a healthy weight
• Quit smoking
• Possibly cholesterol drugs
http://mayoclinic.com/health/high-blood-
Diet
• Reduce your intake of
fats and cholesterols.
• Increase your intake of
fruits and vegetables.
• Add more fiber.
• Eat low-fat or fat-free
dairy products.
• Avoid eating too many
calories.
Exercise
• 30 minutes a day
• 4+ times a week
Cholesterol Drugs
• Talk to your
doctor, and follow
his/her advice.