Introduction to Cholesterol Metabolism



Cholesterol Metabolism

Cholesterol is present in tissues and in plasma either as free cholesterol or as a storage form, combined with along-chain fatty acid as cholesteryl ester. In plasma, both forms are transported in lipoproteins .

Functions of Cholesterol

Cholesterol is an amphipathic lipid and as such is an essential structural

1. Integral Membrane component

2.Bile acids/salts precursor

3.Vitamin D3 precursor

4. Steroid Hormone Precursors as Male sex hormones (testosterone, other androgens) & Female sex hormones (Estrogens) and Adrenal cortex hormones as (glucocorticoides cortisol& Mineralocorticoides aldosterone).

Biosynthesis of Cholesterol

The synthesis and utilization of cholesterol must be tightly regulated in order to prevent over-accumulation and abnormal deposition within the body. Of particular importance clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries.

Cholesterol synthesis in microsomal (endoplasmic reticulum) and cytosol fraction of the cell is responsible for cholesterol synthesis from the two-carbon acetate group of acetyl-CoA. A little more than half the cholesterol of the body arises by synthesis (about 700 mg/dL), and the remainder is provided by the average diet. The liver and intestine account for approximately 10% each of total synthesis in humans. Virtually all tissues containing nucleated cells are capable of cholesterol synthesis, which occurs in the endoplasmic reticulum and the cytosol.

The acetyl-CoA utilized for cholesterol biosynthesis is derived from an oxidation reaction (e.g., fatty acids or pyruvate) in the mitochondria and is transported to the cytoplasm by the same process as that described for fatty acid synthesis. All the reduction reactions of cholesterol biosynthesis use NADPH as a cofactor

Pathway for the movement of acetyl-CoA units from within the mitochondrion to the cytoplasm for use in lipid and cholesterol biosynthesis. Note that the cytoplasmic malic enzyme catalyzed reaction generates NADPH which can be used for reductive biosynthetic reactions such as those of fatty acid and cholesterol synthesis.

The process of cholesterol synthesis has five major steps:

1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)

2. HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2

4. IPP is converted to squalene

5. Squalene is converted to cholesterol.

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Cholesterol biosynthesis begins in the cytosol of liver cells. In the first step of cholesterol biosynthesis 3-hydroxy-3-methylglutaryl CoA is produced from 3 molecules of acetyl-CoA. The first step is catalyzed by the familiar thiolase enzyme which in this case is catalyzing the condensations of 2 acetyl CoA molecules to form acetoacetyl CoA.

The next step is catalyzed by HMG-CoA synthase. This reaction is a second condensation. The product is 3-hydroxy 3-methylglutaryl CoA which is abbreviated HMG-CoA. The third step of cholesterol biosynthesis is the reduction of HMG-CoA to mevalonate. The enzyme that catalyzes this 4 electron reduction is HMG-CoA Reductase. This is the rate determining step of cholesterol biosynthesis.

The phosphorylation reactions are required to solubilize the isoprene intermediates in the pathway.

Isoprene Intermediates in the pathway are used for the synthesis of prenylated proteins as dolichol, coenzyme Q and the side chain of heme a. The abbreviation "PP" (e.g. isopentenyl-PP) stands for pyrophosphate.

Steps of synthesis are as follow

Step 1—Biosynthesis of Mevalonate: HMG-CoA(3-hydroxy-3-methylglutaryl-CoA) is formed by the reactions used in mitochondria to synthesize ketone bodies. However, since cholesterol synthesis is extramitochondrial, the two pathways are distinct. Initially, two molecules of acetyl-CoA condense to form acetoacetyl-CoA catalyzed by cytosolic thiolase. Acetoacetyl-CoA condenses with a further molecule of acetyl-CoA catalyzed by HMG-CoA synthase to form HMG-CoA, which is reduced to mevalonate by NADPH catalyzed by HMG-CoA reductase.

This is the principal regulatory step in the pathway of cholesterol synthesis and is the site of action of the most effective class of cholesterol-lowering drugs, the HMG-CoA reductase inhibitors (statins).

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Step 2—Formation of Isoprenoid Units: Mevalonate is phosphorylated sequentially by ATP by three kinases, and after decarboxylation the active isoprenoid unit, isopentenyl diphosphate, is formed

Step 3—Six Isoprenoid Units Form Squalene: Isopentenyl diphosphate is isomerizes by a shift of the double bond to dimethylallyldiphosphate, then condensed with another molecule of isopentenyldiphosphate to form the ten-carbon intermediate geranyldiphosphate. A further condensation with isopentenyl diphosphate forms farnesyldiphosphate. Two molecules of farnesyl diphosphatecondense at the diphosphate end to form squalene.

Step 4—Formation of Lanosterol: Squalene can fold into a structure that closely resembles the steroid nucleus. Before ring closure occurs, squalene is converted to squalene 2,3-epoxide by a, squalene epoxidase.

Step 5—Formation of Cholesterol: The formation of cholesterol from lanosterol takes place in the membranes of the endoplasmic reticulum

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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 relatively constant level of cholesterol in the blood (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 cholesterol synthesis is exerted near the beginning of the pathway, at the HMG-CoA reductase step The enzyme is controlled by four distinct mechanisms:

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1-feed-back inhibition, HMG-CoA reductase in liver is inhibited by mevalonate, the immediate product of the pathway, and by cholesterol, the main product.

2- control of gene expression, Cholesterol (or a metabolite, eg, oxygenated sterol) represses transcription of the HMG-CoA reductase gene.

3. Hormonal regulation, Regulation of HMGR through covalent modification occurs as a result of phosphorylation and dephosphorylation HMG CoA reductase activity is controlled covalently through the actions of a protein kinase and a phosphoprotein phosphatase The phosphorylated form of the enzyme is inactive, whereas the dephosphorylated form is active.

Insulin or thyroid hormone increases HMG-CoA reductase activity, whereas glucagon or glucocorticoids decrease it.

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4-Inhibition by drugs: The statin drugs, including simvastatin, lovastatin, and are structural analogs of HMG CoA, and are reversible, competitive inhibitors of HMG CoA reductase They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.

Factors Influence The Cholesterol Balance in Tissues

In tissues, cholesterol balance is regulated as follows.

❖ Cell cholesterol increase is due to uptake of cholesterol-containing lipoproteins by receptors, eg, the LDL receptor or the scavenger receptor uptake of free cholesterol from cholesterol-rich lipoproteins to the cell membrane from cholesterol synthesis and from hydrolysis of cholesterylesters by the enzyme cholesteryl ester hydrolase.

❖ Cholesterol is decrease due to efflux of cholesterol from the membrane to HDL, promoted by LCAT (lecithin: cholesterol acyltransferase) enzyme to esterification of cholesterol by ACAT (acyl-CoA: cholesterol acyltransferase); and utilization of cholesterol for synthesis of other steroids, such as hormones, or bile acids in the liver.

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DEGRADATION OF CHOLESTEROL

The ring structure of cholesterol cannot be metabolized and in humans. Rather, the intact sterol nucleus is eliminated from the body by conversion to bile acids and bile salts, Cholesterol is excreted from the body in the bile as cholesterol or bile acids (SALTS)

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Bile Acids are polar derivatives of cholesterol that act as detergents in the intestine, emulsifying dietary fats to make them more accessible to digestive lipases . For cholesterol to be absorbed it must undergo hydrolysis (de-esterification by esterase's) incorporated into micelles be taken up by cholesterol transporter be re-esterified and incorporated into chylomicrons

Cholesterol Transport

❖ Chylomicrons:

o Chylomicrons transport triglycerides from intestine

❖ Very Low Density Lipoproteins (VLDL) and Intermediate Density Lipoproteins (IDL) :

o VLDL produced in liver . Carry cholesterol and triglycerides

❖ Low Density Lipoproteins (LDL)

o LDL result from metabolism of VLDL and IDL and carry cholesterol. LDL are important cause of heart disease

❖ High Density Lipoproteins(HDL)

o HDL is “good” cholesterol. It removes cholesterol and protects against heart disease

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