Cholesterol Synthesis, transport, and excretionAbdul Salam M SofroFaculty of MedicineYARSI University

Learning objectivesBy the end of lectures, students are expected to understand:The process of cholesterol synthesis and excretionCholesterol transport in blood circulation

IntroductionCholesterol present in tissue & in plasma lipoproteins either as free cholesterol or, combined with a long chain FA as cholesteryl esterIt is synthesized in many tissues from acetyl-CoA and is ultimately eliminated from the body in the bile as cholesterol or bile saltsCholesterol is precursor of all other steroids in the body (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)

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 two-carbon acetate group of acetyl-CoA.

Cholesterol's Importance to the Cell MembraneCholesterol is Abundant in Cell MembranesCholesterol Maintains the Integrity of the Cell MembraneCholesterol Helps Maintain the Fluidity of Cell MembranesCholesterol Helps Secure Important Proteins in the Membrane

Biomedical importanceCholesteryl ester is a storage form of cholesterol found in most tissuesIt is transported as cargo in the hydrophobic core of lipoproteinLDL is the mediator of cholesterol & cholesteryl ester uptake into many tissuesFree 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

Acetyl-CoA is the source of all carbon atom in cholesterolFive stages in biosynthesis of cholesterol:Synthesis of Mevalonate, a six-carbon compound, from acetyl-CoAIsoprenoid units are formed from mevalonate by loss of CO2Six isoprenoid units condense to form the intermediate squaleneSqualene cyclisized to parent steroid, lanosterolCholesterol 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-3-methylglutaryl-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 HMG-CoA 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 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 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 acyl-CoA:cholesterol acyltransferase, ACAT 3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDL-mediated reverse transport.

Cholesterol is transported between tissues in plasma lipoproteinsIn human on westernized diets, the total plasma cholesterol is about 5.2 mmol/L (rising with age & wide variations 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 healthIt 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 CholesterolIs 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 CholesterolCarries about one-third to one-fourth of blood cholesterolExperts 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 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 excretionCholesterol must enter the liver & be excreted in 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 the feces after conversion to bile acids, the remainder is excreted as cholesterol.Much of the cholesterol excreted in the bile is reabsorbed & 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)

Cholesterol7-OH-CholesterolCholyl-CoAChenodeoxy-cholyl-CoATaurocholic acidGlycocholic acidDeoxycholic acidLithocholic acidTauro- & glyco-Chenodeoxycholic acid(primary bile acid)(primary bile acid)(primary bile acid)(secondary bile acid)(secondary bile acid)7-hydroxylaseVit. C(-)Bile acidsVit. C defic.Cholesterol(+)

Most bile acids return to the liver in the enterohepatic circulationProduct of fat digestion including cholesterol are absorbed in the first 100 cm of small intestinumPrimary & secondary bile acids are absorbed almost exclusively on the ileum, returning to the liver by way of portal circulation about 98-99% of the bile acids secreted into the intestine (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 through the intestine 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 is synthesized from cholesterol by the liver.