Transcript Lec4 Cholesterol met..

Cholesterol metabolism
Structure of cholesterol
OH is polar part
The ring is non polar part
Cholesterol ester (CE) is
completely non polar
Functions of cholesterol:
1- Enter in the structure of every cell (cell membrane).
2- Gives vitamin D3 by UV radiation
3- Gives bile acids and salts in liver and this is activated by thyroid
hormone.
4- Give steroidal hormones (hormones of adrenal cortex and sex hormones).
Sources of cholesterol in our body:
Exogenous or Dietary source: it is present in egg yolk, meat,
burger, liver and brain.
Endogenous or from synthetic pathway in liver (mainly),
intestine, adrenal cortex, ovaries, testis and skin.
I- Digestion and absorption of dietary cholesterol
•
Digestion occurs mainly in intestine
• Most dietary cholesterol is present in free form (not estrified) with 10-15%
present as cholesterol ester (CE, fatty acid attached to OH at C3). Since free
cholesterol is more absorbable (can penetrate the water layer surrounding the
enterocytes ), so all CE should be converted into free cholesterol
• Cholesterol esterase secreted in pancreatic juice acts on cholesterol ester giving
free cholesterol and fatty acids. Bile salts are necessary for activation of this
enzyme.
esterase
CE
free Cholesterol + FA
In intestinal mucosa, the major
amounts of free cholesterol (about
80-90%) combine with acyl CoA
(active form of fatty acids) to form
cholesterol
esters
which
transported in blood with TAG,
phospholipids and apoprotein to
form lipoprotein chylomicron. The
enzyme that catalyzes cholesterol
esterification in mucosa is ACAT
(Acyl
CoA:
Transferase).
Cholesterol
Acyl
II- Synthesis of cholesterol:
De novo synthesis of cholesterol occurs in all body cells but mainly
in the cytoplasm and ER of liver and intestine. Synthesis also occur
in adrenal cortex, ovary, testis, placenta, skin.
The precursor is acetyl CoA derived from oxidation of glucose in
mitochondrial matrix (as occur in FA synthesis) . SO in fed state
(high CHO diet) the excess acetyl CoA produced from glucose
oxidation is used for biosynthesis of both FA and cholesterol
- Acetyl CoA must be transported from mitochondria to cytoplasm as
citrate (as in fatty acid synthesis).then citrate is cleaved in the
cytoplasm by citrate cleavage system (exactly as occur in FA
synthesis)
Transport of acetyl CoA from mitochondria to cytoplasm:
Mitochondria:
OAA + Acetyl CoA
-CoA
↓ citrate synthase
Citrate
Inner mitochondrial membrane
↓
Citrate
+ CoA, ATP
Cystosol
↓ ATP citrate lyase
OAA + Acetyl CoA
The process of cholesterol synthesis has these major steps:
1. Two molecules of acetyl CoA condense together to form
acetoacetyl CoA .
2. Acetoacetyl CoA condense with third molecule of acetyl CoA to
form hydroxymethyl glutaryl CoA ( HMG-CoA), the enzyme is
cytosolic HMG CoA synthase
3. HMG-CoA is reduced to mevalonate (6C), the enzyme is HMG
CoA reductase which is the key enzyme in the biosynthesis
4. Mevalonate is phosphorylated and decarboxylated to form the
isoprene unit [or called isopentenyl pyroposphate] (5C).
4. Two isoprene units condense to form geranyl pyrophosphate (10
C) which react with another 5C unit to from Farnesyl
pyrophosphate (15C)
5. Two molecules of farnensyl condense to form squalene (30 C)
which cyclise to form Lanosterol
6. Lanosterol is converted into cholesterol by series of reactions.
Mevalonate (6C)
↓phosphprylation and decaboxylation
Isoprene unit (5C) [or called isopentenyl pyroposphate]
↓
Geranyl PP (10 C)
↓
Feransyl PP (15 C)
↓
Squalene (30 C)
↓cyclization
Lanosterol (30 C)
↓ - 3CO2
Cholesterol (27 C)
Cholesterol synthesis
cytoplasmic H MG-CoA synthase (different from that
responsible for ketogenesis)
Regulation of cholesterol synthesis:
HMG- CoA reductase is the key (rate limiting) enzyme in the biosynthesis of
cholesterol.
It is regulated by:
1- Feed back inhibition by cholesterol: Cholesterol (the end product of the
pathway) acts as feed back inhibitor of the pre-existing HMG –CoA reductase as
well as inducing rapid degradation of the enzyme..
2- Drug inhibition: Statins such as atorvastatin (by Pfizer), lovastatin and
simvastatin are drugs with a side chain structurally similar to HMG-CoA so
competitively inhibit HMG-CoA reductase. They are used to decrease cholesterol
levels in patients with hypercholesterolemia.
3- Diet: its activity activated by high CHO and fat diet and inhibited in starvation.
4- Hormonal regulation: insulin stimulate protein phosphatase enzyme which
phosphorylates the enzyme and actives it (dephosphprylated form is the active
form) antiinsulin hormons such as glucagon inactivate the enzyme. (it similar to
regulation of acetyl Co A carboxylase enzyme in FA synthesi)
Degradation of cholesterol
Ring of sterol can’t be metabolized to CO2 & H2O in humans. The
excess cholesterol is eliminated from the body by conversion to bile
acids and bile salts (80-90%) or by secretion into bile (10-20%)
then to intestine for elimination.
Conversion of cholesterol into bile acids and bile salts:
80-90% of cholesterol is converted (oxidized) into bile acids then to
bile salts. This is activated by thyroxin hormone. So hypothyrodism
leads to increased cholesterol in blood.
Bile acids:
Two bile acids are synthesized in
liver from cholesterol by the action
7-α hydroxylase enzyme and then
further hydorxylation and oxidation
of side chain, the produced bile
acids are:
cholic acid and chenodeoxy cholic
acid .
chenodeoxycholic acid and cholic
acid are called primary bile acids.
Synthesis of primary bile acids in the liver (for your knowledge)
OH
OH
Formation of bile salts: Cholic acid and chenodeoxycholic acid
are conjugated in liver with either glycine or taurine (formed from
cysteine amino acid) forming glycocholic acid or taurocholic acid.
Bile salts are carried from the liver to gallbladder, where they are
stored for future use. Bile salts have more effective emulsifying
effect thean bile acids.
Enterohepatic Circulation of Bile Acids and Salts
• Cholic acid, chenodeoxycholic acid and their conjugates in liver
are secreted into intestine to help lipid digestion.
• In intestine, some bile salts are deconjugated to get bile acids.
Some primary bile acids are dehydroxylated by intestinal bacteria to
the secondary bile acids, identified as deoxycholic acid and
lithocholic acid.
• Entrohepatic circulation the bile salts
• 95 % of primary and secondary bile acids and salts are returned
to the liver, where they can be reconjugated with glycine or taurine.
•
5% of bile acids are lost in the feces
Functions of bile salts in fat metabolism:
1. their synthesis and subsequent excretion in the feces represent the
only significant mechanism for the elimination of excess cholesterol.
2. Bile salts and phospholipids solubilize cholesterol in the bile,
thereby preventing the precipitation of cholesterol in the gallbladder.
So deficiency of bile salts leads to cholesterol gallstones.
3. they facilitate the digestion of dietary triacylglycerols by acting as
emulsifying agents that render fats accessible to pancreatic lipases.
4. Activate pancreatic lipase (steapsin) and cholesterol esterase
Disturbances in cholesterol metabolism:
Plasma cholesterol: normal cholesterol level in blood is 150-250 mg/dL (average 200
mg/dL). Plasma cholesterol is derived mainly from liver and intestine.
Hypercholesterolemia: i.e increased cholesterol level in blood than 250 mg/dL:
Causes:
1- Hypothyrodism: lead to decreased conversion of cholesterol into bile acids and
decreased mobilization of cholesterol from blood to tissues.
2- Diabetes: due to increased absorption of dietary cholesterol
3- Diet rich in carbohydrates, and fats: increase the synthesis of cholesterol in liver
due to:
a - Increased the activity of the key enzyme (HMG-CoA reductase).
b - Formation of excess acetyl CoA (from fats and CHO) than the requirements of
kreb’s cycle.
c- insulin secreted after CHO diet will activate the key enzyme (dephosphorylate
it)
4- High cholesterol in diet
Hypocholesterolemia: decrease of cholesterol level in blood below
150 mg/dL:
1- Hyperthyrodism: ↑ thyroid hormone→
a- ↑ oxidation of cholesterol into bile salts.
b- increase mobilization of cholesterol from blood to tissues.
2-Starvation: inhibits cholesterol synthesis by decreasing HMGCoA reductase.
3- Estrogens: decrease cholesterol and prevent atherosclerosis, so,
coronary heart disease rarely occurs in females during reproductive
period of life.
Study question:
High carbohydrate diet may lead to all of the following
EXCEPT:
a) release of insulin which inactivate HMG CoA reductase
b) Hypercholesterolemia
c) Over synthesis of fatty acids and TAG
d) Increased synthesis of acetyl CoA carboxylase