11. Sintesis Kolesterol

7/18/2019 11. Sintesis Kolesterol

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Cholesterol Synthesis, transport, and

excretion

Abdul Salam M Sofro

Faculty of Medicine

YARSI University

Learning objectives

• By the end of lectures, students are

expected to understand: –The process of cholesterol synthesis

and catabolism

–Cholesterol transport in bloodcirculation & excretion

KasusIbu S usia 42 th mengeluh pada dokter

keluarganya bahwa sejak beberapabulan terakhir pemeriksaan profil

lipidnya kurang baik. Kolesterol total

dan trigliseridanya jauh di atas normal,

LDL di atas normal dan HDL cenderung

rendah. Pasien juga mengatakan sdh

tidak makan goreng-gorengan, serta

menghindari makan berlemak, tetapikadar senyawa-senyawa lipid tersebut

belum kembali normal.

Photo by: Lev Olkha

Introduction

• Cholesterol present in tissue & in plasmalipoproteins either as free cholesterol or,combined with a long chain FA as

cholesteryl ester• It is synthesized in many tissues from

acetyl-CoA and is ultimately eliminatedfrom the body in the bile as cholesterol or

bile salts

http://www.gugulipid.com/mechan.htm

Lipid Structure

Cholesterol

Fatty Acids

Glycerol

Triglycerides

Phospholipid: Lecithin

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

several further steps including the loss of threemethyl 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.

Key concepts: synthesis

Primary synthetic sites areextrahepatic, but liver is key regulator

of homeostasis

Normal Cholesterol Metabolism

Key concepts: absorption

Largest source is biliary secretion, not diet.

Normal absorption: 50%

For cholesterol to be absorbed it must:

undergo hydrolysis (de-esterification by

esterases)

be incorporated into micelles

be taken up by cholesterol transporter

be re-esterified and incorporated into

chylomicrons

400 mg/day

1,300 mg/day

17,400 mg/day

Normal Cholesterol Absorption

Plant sterols competeFor cholesterol here

Oil phase

Stage 5

• The conversion of lanosterol to

cholesterol

Regulating Cholesterol 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:

– Reduced activity in fasting animals(reduced synthesis of cholesterol duringfasting)

– Feedback mechanism whereby HMG-CoAreductase in liver in inhibited bymevalonate, the immediate product &cholesterol, the main product of the

pathway (cholesterol metabolite, eg.oxygenated sterol is considered to represstranscription of the HMG-CoA reductasegene

Many factors influence the cholesterol balance

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; andhydrolysis of cholesteryl-ester by the

enzyme cholesteryl ester hydrolase

Decrease is due to:

efflux of cholesterol from the membrane

to lipoproteins of low cholesterol

potential;

esterification of cholesterol by acyl-CoA:cholesterol acyltransferase (ACAT);

utilization of cholesterol for synthesis ofother steroids, such as hormones or bile

acids in liver

The cellular supply of cholesterol is maintained

at a steady level by three distinct mechanisms:

1. Regulation of HMGR activity and levels

2. Regulation of excess intracellular free

cholesterol through the activity of acyl-

CoA:cholesterol acyltransferase, ACAT

3. Regulation of plasma cholesterol levels via LDL

receptor-mediated uptake and HDL-mediatedreverse transport.

Cholesterol is transported

between

tissues in plasma lipoproteins

• In human on westernized diets, the total plasma

cholesterol is about 5.2 mmol/L (rising with age & widevariations between individuals)

• Mostly in esterified form & transported in plasma

lipoproteins being the highest in the LDL (or in VLDL if

VLDL is quantitatively more prominent)

• Dietary cholesterol takes several days to equilibrate with

cholesterol in the plasma & several weeks to equilibrate

with cholesterol of the tissues

Good & bad Cholesterol

and their effect on health

• It is commonly known that a high level of

cholesterol in the blood – hypercholesterolemia –

poses a risk for coronary heart disease (CHD) &

heart attack.

• Cholesterol is insoluble in the blood, it is

transported to and from the cells by carriers

known as lipoproteins

Low-density lipoprotein (LDL) or “Bad

Cholesterol”

• Is the major cholesterol carrier in the blood iftoo much LDL cholesterol circulates in theblood.

• It can slowly build up in the walls of thearteries feeding the heart and brain. Togetherwith other substances it can form plaque, a

thick, hard deposit that can clog those arteries(a condition known as atherosclerosis)

High-density lipoprotein (HDL) or “Good

Cholesterol”

• Carries about 1/3 to 1/4 of blood cholesterol

• Experts think HDL tends to carry cholesterol

away from the arteries and back to the liver,where it is metabolized and removed.

• It is believed that HDL can remove excesscholesterol from plaques and therefore slow

their growth. However, while a high level ofHDL decreases the associated risks, a low levelof HDL cholesterol level may increase the

possibility of stroke or heart attack.

Cholesterol excretion

• Cholesterol must enter the liver & be excretedin the bile as cholesterol or bile acids (salts)

• About 1 g of cholesterol is eliminated from the

body per day. Approx. half is excreted in thefeces after conversion to bile acids, the

remainder is excreted as cholesterol.

• Much of the cholesterol excreted in the bile isreabsorbed & at least some of the cholesterol

that serves as precursor for the fecal sterols is

derived from the intestinal mucosa.

• Coprostanol is the principal sterol in the feces

(formed from cholesterol by the bacteria in

lower intestine)

Cholesterol 7α-OH-Cholesterol

Cholyl-CoA

Chenodeoxy-

cholyl-CoA

Taurocholic acid

Glycocholic acid

Deoxycholic acidLithocholic acid

Tauro- & glyco-

Chenodeoxycholic acid

(primary bile acid)

(secondary bile acid) (secondary bile acid)

7α-hydroxylase

Vit. C

Bile acids

Vit. C defic.

Cholesterol (+)

Most bile acids return to the liver in the

enterohepatic circulation

• Product of fat digestion including cholesterolare absorbed in the first 100 cm of small

intestinum• Primary & secondary bile acids are absorbed

almost exclusively on the ileum, returning tothe liver by way of portal circulation about 98-

99% of the bile acids secreted into theintestine (called enterohepatic circulation)

• Perhaps only as little as 400 mg/d escapes

absorption & eliminated in the feces(represent a major pathway for the elimination

of cholesterol)

• About 3-5 g bile salts can be cycled throughthe intestine 6-10 times with only a small

amount lost in the feces each day an

amount of bile acid equivalent to that lost inthe feces is synthesized from cholesterol by

the liver.

11. Sintesis Kolesterol

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