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Cholesterol Synthesis, transport,
and excretion
Abdul Salam M Sofro
Faculty of MedicineYARSI University
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Learning objectives
By the end of lectures, students are expected tounderstand:
The process of cholesterol synthesis and excretion
Cholesterol transport in blood circulation
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Introduction
Cholesterol present in tissue & in plasmalipoproteins either as free cholesterol or, combinedwith a long chain FA as cholesteryl ester
It is synthesized in many tissues from acetyl-CoA
and is ultimately eliminated from the body in the bileas cholesterol or bile salts
Cholesterol is precursor of all other steroids in thebody (corticosteroids, sex hormones, bile acids &
vitamin D) It is typically a product of animal metabolism
occurs in food of animal origin (egg yolk, meat, liver,brain)
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Slightly less than half of the cholesterol in
the body derives from biosynthesis de novo.
Biosynthesis in the liver accounts for
approximately 10%, and in the intestines
approximately 15%, of the amount producedeach day.
Cholesterol synthesis occurs in the
cytoplasm and microsomes from the two-carbon acetate group of acetyl-CoA.
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Cholesterol's Importance to the Cell
Membrane
Cholesterol is Abundant in Cell
Membranes Cholesterol Maintains the Integrity of the
Cell Membrane
Cholesterol Helps Maintain the Fluidity ofCell Membranes
Cholesterol Helps Secure Important
Proteins in the Membrane
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Biomedical importance
Cholesteryl ester is a storage form of cholesterol
found in most tissues
It is transported as cargo in the hydrophobic core
of lipoprotein
LDL is the mediator of cholesterol & cholesterylester uptake into many tissues
Free cholesterol is removed from tissues by HDL
and transported to liver for conversion to bile acids
(cholesterol is major constituent of gallstones)
Cholesterol plays major role in the genesis of
atherosclerosis
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Acetyl-CoA is the source of all carbon
atom in cholesterol
Five stages in biosynthesis of cholesterol: Synthesis of Mevalonate, a six-carbon compound,
from acetyl-CoA
Isoprenoid units are formed from mevalonate by
loss of CO2 Six isoprenoid units condense to form the
intermediate squalene
Squalene cyclisized to parent steroid, lanosterol
Cholesterol is formed from lanosterol after severalfurther steps including the loss of three methylgroups
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Pathway of cholesterol biosynthesis. Synthesis begins with the transport of acetyl-CoA ffrom
the mitochondrion to the cytosol. The rate limiting step occurs at the 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation
reactions are required to solubilize the isoprenoid intermediates in the pathway.
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Regulating Cholesterol Synthesis
Normal healthy adults synthesize cholesterol
at a rate of approximately 1g/day and
consume approximately 0.3g/day. A relativelyconstant level of cholesterol in the body (150
- 200 mg/dL) is maintained primarily by
controlling the level ofde novo synthesis.
The level of cholesterol synthesis isregulated in part by the dietary intake of
cholesterol.
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Regulation of HMG-CoA reductase:
Reduced activity in fasting animals(reduced synthesis of cholesterol duringfasting)
Feedback mechanism whereby HMG-
CoA reductase in liver in inhibited bymevalonate, the immediate product &cholesterol, the main product of thepathway (cholesterol metabolite, eg.oxygenated sterol is considered torepress transcription of the HMG-CoAreductase gene
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Many factors influence the cholesterolbalance in tissues:
Increase is due to uptake of cholesterol-
containing lipoproteins by receptors;
uptake of free cholesterol from
cholesterol-rich lipoproteins to the cell
membrane; cholesterol synthesis; and
hydrolysis of cholesteryl-ester by theenzyme cholesteryl ester hydrolase
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Decrease is due to efflux of cholesterolfrom the membrane to lipoproteins of low
cholesterol potential; esterification of
cholesterol by acyl-CoA:cholesterolacyltransferase (ACAT); and utilization of
cholesterol for synthesis of other steroids,
such as hormones or bile acids in liver
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The cellular supply of cholesterol is
maintained at a steady level by three distinctmechanisms:
1. Regulation of HMGR activity and levels
2. Regulation of excess intracellular freecholesterol through the activity of acyl-CoA:cholesterol acyltransferase, ACAT
3. Regulation of plasma cholesterol levels viaLDL receptor-mediated uptake and HDL-mediated reverse transport.
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Cholesterol is transported between
tissues in plasma lipoproteins
In human on westernized diets, the total plasmacholesterol is about 5.2 mmol/L (rising with age & wide
variations between individuals)
Mostly in esterified form & transported in plasmalipoproteins being the highest in the LDL (or in VLDLif VLDL is quantitatively more prominent)
Dietary cholesterol takes several days to equilibrate withcholesterol in the plasma & several weeks to equilibrate
with cholesterol of the tissues
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Good & bad Cholesterol and their effect
on health
It is commonly known that a high level ofcholesterol in the bloodhypercholesterolemiaposes a risk for coronary heart disease (CHD)
& heart attack.
Cholesterol is insoluble in the blood, it istransported to and from the cells by carriers
known as lipoproteins
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Low-density lipoprotein (LDL) or BadCholesterol
Is the major cholesterol carrier in the blood iftoo much LDL cholesterol circulates in theblood.
It can slowly build up in the walls of the arteriesfeeding the heart and brain. Together with othersubstances it can formplaque, a thick, harddeposit that can clog those arteries (a conditionknown as atherosclerosis)
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High-density lipoprotein (HDL) or GoodCholesterol
Carries about one-third to one-fourth of bloodcholesterol
Experts think HDL tends to carry cholesterol awayfrom the arteries and back to the liver, where it ismetabolized and removed.
It is believed that HDL can remove excess cholesterolfrom plaques and therefore slow their growth. However,
while a high level of HDL decreases the associated risks,a low level of HDL cholesterol level may increase thepossibility of stroke or heart attack.
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Cholesterol excretion
Cholesterol must enter the liver & be excreted in thebile as cholesterol or bile acids (salts)
About 1 g of cholesterol is eliminated from the body
per day. Approx. half is excreted in the feces afterconversion to bile acids, the remainder is excreted ascholesterol.
Much of the cholesterol excreted in the bile isreabsorbed & at least some of the cholesterol thatserves as precursor for the fecal sterols is derived fromthe intestinal mucosa.
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Coprostanol is the principal sterol in the feces(formed from cholesterol by the bacteria inlower intestine)
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Cholesterol 7-OH-Cholesterol
Cholyl-CoA
Chenodeoxy-
cholyl-CoA
Taurocholic acid
Glycocholic acid
Deoxycholic acidLithocholic acid
Tauro- & glyco-
Chenodeoxycholic acid
(primary bile acid)
(primary bile acid)
(primary bile acid)
(secondary bile acid) (secondary bile acid)
7-hydroxylase
Vit. C
(-)
Bile acids
Vit. C defic.
Cholesterol (+)
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Most bile acids return to the liver in the
enterohepatic circulation
Product of fat digestion including cholesterol areabsorbed in the first 100 cm of small intestinum
Primary & secondary bile acids are absorbed
almost exclusively on the ileum, returning to theliver by way of portal circulation about 98-99%of the bile acids secreted into the intestine(called enterohepatic circulation)
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Perhaps only as little as 400 mg/d escapesabsorption & eliminated in the feces (represent amajor pathway for the elimination of cholesterol)
About 3-5 g bile salts can be cycled through theintestine 6-10 times with only a small amount
lost in the feces each day an amount of bile
acid equivalent to that lost in the feces issynthesized from cholesterol by the liver.
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