Cholesterol Cholesterol Synthesis, Synthesis,

transport, and transport, and excretionexcretion

Abdul Salam M SofroAbdul Salam M SofroFaculty of MedicineFaculty of Medicine

YARSI UniversityYARSI University

Learning objectivesLearning objectives

By the end of lectures, students are By the end of lectures, students are expected to understand:expected to understand: The process of cholesterol synthesis The process of cholesterol synthesis

and excretionand excretion Cholesterol transport in blood Cholesterol transport in blood

circulationcirculation

IntroductionIntroduction Cholesterol present in tissue & in plasma Cholesterol present in tissue & in plasma

lipoproteins either as free cholesterol or, lipoproteins either as free cholesterol or, combined with a long chain FA as cholesteryl combined with a long chain FA as cholesteryl esterester

It is synthesized in many tissues from acetyl-It is synthesized in many tissues from acetyl-CoA and is ultimately eliminated from the CoA and is ultimately eliminated from the body in the bile as cholesterol or bile saltsbody in the bile as cholesterol or bile salts

Cholesterol is precursor of all other steroids in Cholesterol is precursor of all other steroids in the body (corticosteroids, sex hormones, bile the body (corticosteroids, sex hormones, bile acids & vitamin D)acids & vitamin D)

It is typically a product of animal metabolism It is typically a product of animal metabolism occurs in food of animal origin (egg yolk, occurs in food of animal origin (egg yolk, meat, liver, brain) meat, liver, brain)

Slightly less than half of the cholesterol Slightly less than half of the cholesterol in the body derives from biosynthesis in the body derives from biosynthesis de novode novo. .

Biosynthesis in the liver accounts for Biosynthesis in the liver accounts for approximately 10%, and in the approximately 10%, and in the intestines approximately 15%, of the intestines approximately 15%, of the amount produced each day. amount produced each day.

Cholesterol synthesis occurs in the Cholesterol synthesis occurs in the cytoplasm and microsomes from the cytoplasm and microsomes from the two-carbon acetate group of acetyl-two-carbon acetate group of acetyl-CoA. CoA.

Biomedical importanceBiomedical importance Cholesteryl ester is a storage form of Cholesteryl ester is a storage form of

cholesterol found in most tissuescholesterol found in most tissues It is transported as cargo in the hydrophobic It is transported as cargo in the hydrophobic

core of lipoproteincore of lipoprotein LDL is the mediator of cholesterol & LDL is the mediator of cholesterol &

cholesteryl ester uptake into many tissuescholesteryl ester uptake into many tissues Free cholesterol is removed from tissues by Free cholesterol is removed from tissues by

HDL and transported to liver for conversion HDL and transported to liver for conversion to bile acids (cholesterol is major to bile acids (cholesterol is major constituent of gallstones)constituent of gallstones)

Cholesterol plays major role in the genesis Cholesterol plays major role in the genesis of atherosclerosis of atherosclerosis

Acetyl-CoA is the source of all Acetyl-CoA is the source of all carbon atom in cholesterolcarbon atom in cholesterol

Five stages in biosynthesis of Five stages in biosynthesis of cholesterol:cholesterol: Synthesis of Mevalonate, a six-carbon Synthesis of Mevalonate, a six-carbon

compound, from acetyl-CoAcompound, from acetyl-CoA Isoprenoid units are formed from mevalonate Isoprenoid units are formed from mevalonate

by loss of CO2by loss of CO2 Six isoprenoid units condense to form the Six isoprenoid units condense to form the

intermediate squaleneintermediate squalene Squalene cyclisized to parent steroid, Squalene cyclisized to parent steroid,

lanosterollanosterol Cholesterol is formed from lanosterol after Cholesterol is formed from lanosterol after

several further steps including the loss of several further steps including the loss of three methyl groupsthree methyl groups

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.

Regulating Cholesterol Regulating Cholesterol Synthesis Synthesis

Normal healthy adults synthesize cholesterol at a rate of approximately 1g/day and consume approximately 0.3g/day. A relatively constant level of cholesterol in the body (150 - 200 mg/dL) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol.

Regulation of HMG-CoA reductase:Regulation of HMG-CoA reductase: Reduced activity in fasting animals Reduced activity in fasting animals

(reduced synthesis of cholesterol (reduced synthesis of cholesterol during fasting)during fasting)

Feedback mechanism whereby HMG-Feedback mechanism whereby HMG-CoA reductase in liver in inhibited by CoA reductase in liver in inhibited by mevalonate, the immediate product mevalonate, the immediate product & cholesterol, the main product of & cholesterol, the main product of the pathway (cholesterol metabolite, the pathway (cholesterol metabolite, eg. oxygenated sterol is considered eg. oxygenated sterol is considered to repress transcription of the HMG-to repress transcription of the HMG-CoA reductase geneCoA reductase gene

Many factors influence the cholesterol Many factors influence the cholesterol balance in tissues:balance in tissues: Increase is due to uptake of Increase is due to uptake of

cholesterol-containing lipoproteins cholesterol-containing lipoproteins by receptors; uptake of free by receptors; uptake of free cholesterol from cholesterol-rich cholesterol from cholesterol-rich lipoproteins to the cell membrane; lipoproteins to the cell membrane; cholesterol synthesis; and hydrolysis cholesterol synthesis; and hydrolysis of cholesteryl-ester by the enzyme of cholesteryl-ester by the enzyme cholesteryl ester hydrolasecholesteryl ester hydrolase

Decrease is due to efflux of Decrease is due to efflux of cholesterol from the membrane to cholesterol from the membrane to lipoproteins of low cholesterol lipoproteins of low cholesterol potential; esterification of potential; esterification of cholesterol by acyl-CoA:cholesterol cholesterol by acyl-CoA:cholesterol acyltransferase (ACAT); and acyltransferase (ACAT); and utilization of cholesterol for utilization of cholesterol for synthesis of other steroids, such as synthesis of other steroids, such as hormones or bile acids in liverhormones or bile acids in liver

The cellular supply of cholesterol is The cellular supply of cholesterol is maintained at a steady level by three maintained at a steady level by three distinct mechanisms: distinct mechanisms:

1.1. Regulation of HMGR activity and levels Regulation of HMGR activity and levels 2.2. Regulation of excess intracellular free Regulation of excess intracellular free

cholesterol through the activity of acyl-cholesterol through the activity of acyl-CoA:cholesterol acyltransferase, ACAT CoA:cholesterol acyltransferase, ACAT

3.3. Regulation of plasma cholesterol levels Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and via LDL receptor-mediated uptake and HDL-mediated reverse transport. HDL-mediated reverse transport.

Cholesterol is transported Cholesterol is transported between tissues in plasma between tissues in plasma

lipoproteinslipoproteins In human on westernized diets, the total In human on westernized diets, the total

plasma cholesterol is about 5.2 mmol/L (rising plasma cholesterol is about 5.2 mmol/L (rising with age & wide variations between with age & wide variations between individuals)individuals)

Mostly in esterified form & transported in Mostly in esterified form & transported in plasma lipoproteins being the highest in the plasma lipoproteins being the highest in the LDL (or in VLDL if VLDL is quantitatively more LDL (or in VLDL if VLDL is quantitatively more prominent)prominent)

Dietary cholesterol takes several days to Dietary cholesterol takes several days to equilibrate with cholesterol in the plasma & equilibrate with cholesterol in the plasma & several weeks to equilibrate with cholesterol of several weeks to equilibrate with cholesterol of the tissuesthe tissues

Good & bad Cholesterol and Good & bad Cholesterol and their effect on healththeir effect on health

It is commonly known that a It is commonly known that a high high level of cholesterollevel of cholesterol in the blood – in the blood – hypercholesterolemia – poses a risk hypercholesterolemia – poses a risk for coronary heart disease (CHD) & for coronary heart disease (CHD) & heart attack.heart attack.

Cholesterol is insoluble in the blood, Cholesterol is insoluble in the blood, it is transported to and from the cells it is transported to and from the cells by carriers known as lipoproteinsby carriers known as lipoproteins

Low-density lipoprotein (LDL) or “Bad Low-density lipoprotein (LDL) or “Bad Cholesterol”Cholesterol”

Is the major cholesterol carrier in the Is the major cholesterol carrier in the blood if too much LDL cholesterol blood if too much LDL cholesterol circulates in the blood.circulates in the blood.

It can slowly build up in the walls of It can slowly build up in the walls of the arteries feeding the heart and the arteries feeding the heart and brain. Together with other brain. Together with other substances it can form substances it can form plaqueplaque, a , a thick, hard deposit that can clog thick, hard deposit that can clog those arteries (a condition known as those arteries (a condition known as atherosclerosisatherosclerosis))

High-density lipoprotein (HDL) or High-density lipoprotein (HDL) or “Good Cholesterol”“Good Cholesterol”

Carries about one-third to one-fourth of Carries about one-third to one-fourth of blood cholesterolblood cholesterol

Experts think HDL tends to carry Experts think HDL tends to carry cholesterol away from the arteries and back cholesterol away from the arteries and back to the liver, where it is metabolized and to the liver, where it is metabolized and removed.removed.

It is believed that HDL can remove excess It is believed that HDL can remove excess cholesterol from plaques and therefore slow cholesterol from plaques and therefore slow their growth. However, while a high level of their growth. However, while a high level of HDL decreases the associated risks, a low HDL decreases the associated risks, a low level of HDL cholesterol level may increase level of HDL cholesterol level may increase the possibility of stroke or heart attack.the possibility of stroke or heart attack.

Cholesterol excretionCholesterol excretion Cholesterol must enter the liver & be Cholesterol must enter the liver & be

excreted in the bile as cholesterol or bile excreted in the bile as cholesterol or bile acids (salts)acids (salts)

About 1 g of cholesterol is eliminated from About 1 g of cholesterol is eliminated from the body per day. Approx. half is excreted in the body per day. Approx. half is excreted in the feces after conversion to bile acids, the the feces after conversion to bile acids, the remainder is excreted as cholesterol.remainder is excreted as cholesterol.

Much of the cholesterol excreted in the bile is Much of the cholesterol excreted in the bile is reabsorbed & at least some of the cholesterol reabsorbed & at least some of the cholesterol that serves as precursor for the fecal sterols that serves as precursor for the fecal sterols is derived from the intestinal mucosa.is derived from the intestinal mucosa.

Coprostanol is the principal sterol in Coprostanol is the principal sterol in the feces (formed from cholesterol the feces (formed from cholesterol by the bacteria in lower intestine)by the bacteria in lower intestine)

Cholesterol 7α-OH-Cholesterol

Cholyl-CoAChenodeoxy-cholyl-CoA

Taurocholic acid

Glycocholic acid

Deoxycholic acid Lithocholic acid

Tauro- & glyco-Chenodeoxycholic acid

(primary bile acid)

(primary bile acid)

(primary bile acid)

(secondary bile acid) (secondary bile acid)

7α-hydroxylase

Vit. C

(-)

Bile acidsVit. C defic.

Cholesterol (+)

Most bile acids return to the Most bile acids return to the liver in the enterohepatic liver in the enterohepatic

circulationcirculation Product of fat digestion including Product of fat digestion including

cholesterol are absorbed in the first cholesterol are absorbed in the first 100 cm of small intestinum100 cm of small intestinum

Primary & secondary bile acids are Primary & secondary bile acids are absorbed almost exclusively on the absorbed almost exclusively on the ileum, returning to the liver by way of ileum, returning to the liver by way of portal circulation about 98-99% of portal circulation about 98-99% of the bile acids secreted into the the bile acids secreted into the intestine (called intestine (called enterohepatic enterohepatic circulationcirculation))

Perhaps only as little as 400 mg/d Perhaps only as little as 400 mg/d escapes absorption & eliminated in the escapes absorption & eliminated in the feces (represent a major pathway for feces (represent a major pathway for the elimination of cholesterol)the elimination of cholesterol)

About 3-5 g bile salts can be cycled About 3-5 g bile salts can be cycled through the intestine 6-10 times with through the intestine 6-10 times with only a small amount lost in the feces only a small amount lost in the feces each day an amount of bile acid each day an amount of bile acid equivalent to that lost in the feces is equivalent to that lost in the feces is synthesized from cholesterol by the synthesized from cholesterol by the liver.liver.