[Www.indowebster.com]-Cholesterol Synthesis- Transport- And Excretion

7/28/2019 [Www.indowebster.com]-Cholesterol Synthesis- Transport- And Excretion

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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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[Www.indowebster.com]-Cholesterol Synthesis- Transport- And Excretion

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