cholesterol synthesis-stepsandregulation-

Information about cholesterol synthesis-stepsandregulation-

Published on October 14, 2014

Author: drmustansar

Source: authorstream.com

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Cholesterol Synthesis- Steps and regulation : Cholesterol Synthesis- Steps and regulation Cholesterol Introduction: Cholesterol Introduction 10/14/2014 Biochemistry for medics 3 Cholesterol is the major sterol in the animal tissues. Cholesterol is present in tissues and in plasma either as free cholesterol or as a storage form, combined with a long-chain fatty acid as cholesteryl ester. In plasma, both forms are transported in lipoproteins Plasma low-density lipoprotein (LDL) is the vehicle of uptake of cholesterol and cholesteryl ester into many tissues. Free cholesterol is removed from tissues by plasma high-density lipoprotein (HDL) and transported to the liver, where it is eliminated from the body either unchanged or after conversion to bile acids in the process known as reverse cholesterol transport . Structure of cholesterol: Structure of cholesterol 10/14/2014 Biochemistry for medics 4 The structure of cholesterol consists of four fused rings (The rings in steroids are denoted by the letters A, B, C, and D.), with the carbons numbered in the sequence, and an eight numbered, and branched hydrocarbon chain attached to the D ring. Cholesterol contains two angular methyl groups: the C-19 methyl group is attached to C-10, and the C-18 methyl group is attached to C-13. The C-18 and C-19 methyl groups of cholesterol lie above the plane containing the four rings. Structure of cholesterol (contd.): Structure of cholesterol (contd.) 10/14/2014 Biochemistry for medics 5 Steroids with 8 to 10 carbon atoms in the side chain and an alcohol hydroxyl group at C-3 are classified as sterols. Much of the plasma cholesterol is in the esterified form (with a fatty acid attached at carbon 3), which makes the structure even more hydrophobic . Functions of cholesterol: Functions of cholesterol 10/14/2014 Biochemistry for medics 6 Cholesterol is the most abundant sterol in humans and performs a number of essential functions. For example- It is a major constituent of the plasma membrane and of plasma lipoproteins. It is a precursor of bile salts, It is a precursor of steroid hormones that include adrenocortical hormones, sex hormones, placental hormones etc Also a precursor of vitamin D, cardiac glycosides, Sitosterol of the plant kingdom, and some alkaloids. It is required for the nerve transmission. Cholesterol is widely distributed in all cells of the body but particularly abundant in nervous tissue. Sources of cholesterol: Sources of cholesterol 10/14/2014 Biochemistry for medics 7 Cholesterol is derived from diet de novo synthesis and from the hydrolysis of cholesteryl esters. A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), 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. Steps of synthesis of cholesterol: Steps of synthesis of cholesterol 10/14/2014 Biochemistry for medics 8 Acetyl co A acts as a precursor of cholesterol. All 27 carbon atoms of cholesterol are derived from acetyl CoA in a three-stage synthetic process Stage one is the synthesis of Isopentenyl pyrophosphate, an activated isoprene unit that is the key building block of cholesterol. Stage two is the condensation of six molecules of Isopentenyl pyrophosphate to form Squalene. In stage three, Squalene cyclizes in an astounding reaction and the tetracyclic product is subsequently converted into cholesterol. STAGE 1 OF CHOLESTEROL SYNTHESIS: STAGE 1 OF CHOLESTEROL SYNTHESIS 10/14/2014 Biochemistry for medics 9 The first stage in the synthesis of cholesterol is the formation of Isopentenyl pyrophosphate from acetyl CoA. This set of reactions, which takes place in the cytosol, starts with the formation of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) from acetyl CoA. 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, that is reduced to mevalonate by NADPH catalyzed by HMG-CoA reductase. PowerPoint Presentation: 10/14/2014 Biochemistry for medics 10 The synthesis of mevalonate is the committed step in cholesterol formation. The enzyme catalyzing this irreversible step, 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is an important control site in cholesterol biosynthesis, and is the site of action of the most effective class of cholesterol-lowering drugs, the HMG-CoA reductase inhibitors (statins). STAGE 1 OF CHOLESTEROL SYNTHESIS (contd.): STAGE 1 OF CHOLESTEROL SYNTHESIS (contd.) 10/14/2014 Biochemistry for medics 11 Mevalonate is converted into 3-isopentenyl pyrophosphate in three consecutive reactions requiring ATP. Decarboxylation yields Isopentenyl pyrophosphate, an activated isoprene unit that is a key building block for many important biomolecules. STAGE -2 OF CHOLESTEROL SYNTHESIS: STAGE -2 OF CHOLESTEROL SYNTHESIS 10/14/2014 Biochemistry for medics 12 Synthesis of Squalene Squalene (C30) is synthesized from six molecules of Isopentenyl Pyrophosphate (C5) and the reaction sequence is- C5 C10 C15 C30 This stage in the synthesis of cholesterol starts with the isomerization of isopentenyl pyrophosphate to dimethylallyl pyrophosphate. Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl diphosphate, then condensed with another molecule of isopentenyl diphosphate to form the ten-carbon intermediate geranyl diphosphate. PowerPoint Presentation: 10/14/2014 Biochemistry for medics 13 STAGE -2 OF CHOLESTEROL SYNTHESIS (contd.): STAGE -2 OF CHOLESTEROL SYNTHESIS (contd.) 10/14/2014 Biochemistry for medics 14 A further condensation with isopentenyl diphosphate forms farnesyl diphosphate. Two molecules of farnesyl diphosphate condense at the diphosphate end to form squalene. Initially, inorganic pyrophosphate is eliminated, forming presqualene diphosphate, which is then reduced by NADPH with elimination of a further inorganic pyrophosphate molecule. Stage-3- Formation of Cholesterol from squalene: Stage-3- Formation of Cholesterol from squalene 10/14/2014 Biochemistry for medics 15 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 mixed-function oxidase in the endoplasmic reticulum, squalene epoxidase. The methyl group on C 14 is transferred to C 13 and that on C 8 to C 14 as cyclization occurs, catalyzed by oxidosqualene: lanosterol cyclase. The newly formed cyclized structure is Lanosterol Stage-3- Formation of Cholesterol from squalene (contd.): Stage-3- Formation of Cholesterol from squalene (contd.) 10/14/2014 Biochemistry for medics 16 The formation of cholesterol from lanosterol takes place in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus and side chain . The methyl groups on C 14 and C 4 are removed to form 14-desmethyl lanosterol and then zymosterol. The double bond at C 8 –C 9 is subsequently moved to C 5 –C 6 in two steps, forming desmosterol. Finally, the double bond of the side chain is reduced, producing cholesterol. REGULATION OF CHOLESTEROL BIOSYNTHESIS: REGULATION OF CHOLESTEROL BIOSYNTHESIS 10/14/2014 Biochemistry for medics 17 Regulation of cholesterol synthesis is exerted near the beginning of the pathway, at the HMG-CoA reductase step. Following mechanisms are involved at the regulatory step- Competitive inhibition Feed back inhibition Covalent modification(Role of hormones) Sterol mediated regulation of transcription REGULATION OF CHOLESTEROL BIOSYNTHESIS: REGULATION OF CHOLESTEROL BIOSYNTHESIS 10/14/2014 Biochemistry for medics 18 Competitive inhibition Statins (Lovastatin, Mevastatin, Atorva Statin etc.) are the reversible competitive inhibitors of HMG Co A reductase. They are used to decrease plasma cholesterol levels in patients of hypercholesterolemia. REGULATION OF CHOLESTEROL BIOSYNTHESIS: REGULATION OF CHOLESTEROL BIOSYNTHESIS 10/14/2014 Biochemistry for medics 19 Feed back inhibition HMG Co A reductase is inhibited by Mevalonate and Cholesterol. Mevalonate is the immediate product of HMG Co A reductase catalyzed reaction whereas Cholesterol is the ultimate product of the reaction pathway. REGULATION OF CHOLESTEROL BIOSYNTHESIS: REGULATION OF CHOLESTEROL BIOSYNTHESIS 10/14/2014 Biochemistry for medics 20 Covalent modification (Role of hormones) Phosphorylation decreases the activity of the reductase. Glucagon favors formation of the inactive (phosphorylated form) form, hence decreases the rate of cholesterol synthesis In contrast , insulin favors formation of the active(dephosphorylated )form of HMG Co A reductase and results in an increase in the rate of cholesterol synthesis Cholesterol synthesis ceases when the ATP level is low REGULATION OF CHOLESTEROL BIOSYNTHESIS: REGULATION OF CHOLESTEROL BIOSYNTHESIS 10/14/2014 Biochemistry for medics 21 Sterol mediated regulation of transcription The synthesis of cholesterol is also regulated by the amount of cholesterol taken up by the cells during lipoprotein metabolism. Chylomicron remnants internalized by liver cells, and low density lipoproteins internalized by liver cells and peripheral tissues provide cholesterol which causes a decrease in the transcription of HMG CoA reductase gene, leading to a decrease in cholesterol synthesis. The rate of synthesis of reductase mRNA is controlled by the sterol regulatory element binding protein (SREBP). REGULATION OF CHOLESTEROL BIOSYNTHESIS: REGULATION OF CHOLESTEROL BIOSYNTHESIS 10/14/2014 Biochemistry for medics 22 Sterol mediated regulation of transcription This transcription factor binds to a short DNA sequence called the sterol regulatory element (SRE) on the 5 side of the reductase gene. In its inactive state, the SREBP is anchored to the endoplasmic reticulum or nuclear membrane. When cholesterol levels fall, the protein is released The released protein migrates to the nucleus and binds the SRE of the HMG-CoA reductase gene, to enhance transcription. When cholesterol levels rise, the proteolytic release of the SREBP is blocked, and the SREBP in the nucleus is rapidly degraded Transport of cholesterol: Transport of cholesterol 10/14/2014 Biochemistry for medics 23 Cholesterol is transported in plasma in lipoproteins, and in humans the highest proportion is found in LDL. Cholesteryl ester in the diet is hydrolyzed to cholesterol, which is then absorbed by the intestine together with dietary unesterified cholesterol and other lipids. With cholesterol synthesized in the intestines, it is then incorporated into chylomicrons. Ninety-five percent of the chylomicron cholesterol is delivered to the liver in chylomicron remnants, Most of the cholesterol secreted by the liver in VLDL is retained during the formation of IDL and ultimately LDL, which is taken up by the LDL receptor in liver and extra hepatic tissues. Uptake of LDL cholesterol : Uptake of LDL cholesterol 10/14/2014 Biochemistry for medics 24 The LDLs (containing cholesteryl esters) are taken up by cells by a process known as receptor-mediated endocytosis. The LDL receptor mediates this endocytosis and is important to cholesterol metabolism. After LDL binding to the LDL receptor, the ligand-receptor complexes cluster on the plasma membrane in coated pits, which then invaginate forming coated vesicles. These coated vesicles are internalized and clathrin, the protein composing the lattice in membrane coated pits, is removed. Uptake of LDL cholesterol : Uptake of LDL cholesterol 10/14/2014 Biochemistry for medics 25 These vesicles are now called endosomes and these endosomes fuse with the lysosome. The LDL receptor–containing membrane buds off and is recycled to the plasma membrane. Fusion of the lysosome and endosome releases lysosomal proteases that degrade the apoproteins into amino acids. Lysosomal enzymes also hydrolyze the cholesteryl esters to free cholesterol and fatty acids. The free cholesterol is released into the cell’s cytoplasm, and this free cholesterol is then available to be used by the cell. Uptake of LDL cholesterol: Uptake of LDL cholesterol 10/14/2014 Biochemistry for medics 26 Excess cholesterol is reesterified by acyl-CoA: cholesterol acyltransferase (ACAT), which uses fatty acyl-CoA as the source of activated fatty acid. Free cholesterol affects cholesterol metabolism by inhibiting cholesterol biosynthesis. Cholesterol inhibits the enzyme hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase), which catalyzes an early rate-limiting step in cholesterol biosynthesis. In addition, free cholesterol inhibits the synthesis of the LDL receptor, thus limiting the amount of LDLs that are taken up by the cell. Uptake of LDL cholesterol: Uptake of LDL cholesterol 10/14/2014 Biochemistry for medics 27 Receptor mediated endocytosis of LDL Variation of serum cholesterol levels: Variation of serum cholesterol levels 10/14/2014 Biochemistry for medics 28 The normal serum cholesterol concentration ranges between 150- 220 mg/dl High cholesterol concentration is found in- Diabetes mellitus Nephrotic syndrome Obstructive jaundice Familial hypercholesterolemia Biliary cirrhosis Hypothyroidism Variation of serum cholesterol levels: Variation of serum cholesterol levels 10/14/2014 Biochemistry for medics 29 Hypocholesterolemia- Low serum cholesterol concentration is observed in- Hyperthyroidism Malnutrition Malabsorption Anemia Physiologically lower levels are found in children Persons on cholesterol lowering drugs Hypercholesterolemia and the consequences : Hypercholesterolemia and the consequences 10/14/2014 Biochemistry for medics 30 Atherosclerosis is characterized by the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins into the artery wall. Diseases in which prolonged elevated levels of VLDL, IDL, chylomicron remnants, or LDL occur in the blood are often accompanied by premature or more severe atherosclerosis. Hypolipidemic drugs: Hypolipidemic drugs 10/14/2014 Biochemistry for medics 31 Statins - The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. Fibrates such as Clofibrate and gemfibrozil act mainly to lower plasma triacylglycerols by decreasing the secretion of triacylglycerol and cholesterol-containing VLDL by the liver. Ezetimibe - ezetimibe, reduces blood cholesterol levels by inhibiting the absorption of cholesterol by the intestine Bile Acid Sequestrants (Resins)- Bile acid sequestrants bind bile acids in the intestine and promote their excretion in the stool. To maintain the bile acid pool size, the liver diverts cholesterol to bile acid synthesis Hypolipidemic drugs: Hypolipidemic drugs 10/14/2014 Biochemistry for medics 32 Bile acid sequestrants (contd.)- The decreased hepatic intracellular cholesterol content results in up regulation of the LDL receptor and enhanced LDL clearance from the plasma. Bile acid sequestrants, including Cholestyramine, Colestipol, and colesevelam. Omega 3 Fatty Acids (Fish Oils) -The most widely used n-3 PUFAs for the treatment of hyperlipidemia are the two active molecules in fish oil: Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA). Niacin inhibits the release of free fatty acids from adipose tissue which leads to a decrease of free fatty acids entering the liver and decreased VLDL synthesis in the liver. Role of diet in regulating cholesterol levels: Role of diet in regulating cholesterol levels 10/14/2014 Biochemistry for medics 33 Polyunsaturated fatty acids have a cholesterol lowering effect There is the up-regulation of LDL receptors by poly- and monounsaturated as compared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extra hepatic tissues at a slower rate than are larger particles and thus may be regarded as atherogenic. Lifestyle and the Serum Cholesterol Levels : Lifestyle and the Serum Cholesterol Levels 10/14/2014 Biochemistry for medics 34 Additional factors considered to play a part in coronary heart disease include high blood pressure, smoking, male gender, obesity (particularly abdominal obesity) and lack of exercise Premenopausal women appear to be protected against many of these deleterious factors, and this is thought to be related to the beneficial effects of estrogen. There is an association between moderate alcohol consumption and a lower incidence of coronary heart disease. This may be due to elevation of HDL concentrations resulting from increased synthesis of apo A-I Regular exercise lowers plasma LDL but raises HDL.

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