Cholesterol Synthesis, transport, and excretion

Abdul Salam M Sofro Faculty of Medicine YARSI University

Introduction
Cholesterol present in tissue & in plasma lipoproteins 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 eliminated from the body in the bile as cholesterol or bile salts Cholesterol is precursor of all other steroids in the body (corticosteroids, sex hormons, bile acids & vitamin D) It is typically a product of animal metabolism occurs in food of animal origin (egg yolk, meat, liver, brain)

 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 produced each day. Cholesterol synthesis occurs in the cytoplasm and microsomes from the twocarbon acetate group of acetyl-CoA.

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 & cholesteryl ester 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 atheroclerosis

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 three 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-3methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation reactions are required to solubilize the isoprenoid intermediates in the pathway.

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

 Many factors influence the cholesterol balance in tissues: Increase is due to uptake of cholesterolcontaining lipoproteins by receptors; uptake of free cholesterol from cholesterol-rich lipoproteins to the cell membrane; cholesterol synthesis; and hydrolysis 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); and utilization of cholesterol for synthesis of other 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 acylCoA:cholesterol acyltransferase, ACAT 3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDLmediated reverse transport.

Good and Bad Cholesterols and their affect on Health.

It is commonly known that a high level of cholesterol in the blood hypercholesterolemia- poses a risk for coronary heart disease and 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. If too much LDL cholesterol circulates in the blood it can slowly build up in the walls of the arteries feeding the heart and brain. Together with 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 one-third to one-fourth of blood cholesterol Experts think HDL tends to carry cholesterol away from the arteries and back to the liver, where it is metabolised and removed. It is believed that HDL can remove excess cholesterol from 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 the possibility of stroke or heart attack.

Cholesterol Excretion
Cholesterol must enter the liver and excreted in the bile as cholesterol or bile acids (salts) About 1 g cholesterol is eliminated from the body per day Much of cholesterol secreted in the bile is reabsorbed 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

7-hydroxycholesterol

Cholyl-CoA

Chenodeoxycholyl-CoA Tauro & glycochenodeoxycholic acid

Taurocholic acid

Glycocholic acid

Deoxycholic acid

Lythocholic acid