lipoproteins and cholesterol الفريق الطبي األكاديمي Done By :- Obadah Abubaker & Yousef Qandeel

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1 lipoproteins and cholesterol الفريق الطبي األكاديمي Done By :- Obadah Abubaker & Yousef Qandeel لكية الطب البرشي البلقاء التطبيقية / املركز /

2 Lipoproteins and cholesterol In this lecture we are going to talk about فيعني "طالعة" (0-4:19 min) First of all, what is cholesterol? Cholesterol is a fat (lipid) molecule and is the parent compound of all steroid hormones. It is not a bad molecule although people have an idea that cholesterol is very bad molecule but indeed is very useful molecule, but if we have it in high concentration then it will cause problems, but under normal physiological conditions the existence of cholesterol is very important. Why? 1- One of the component of the cell membrane 2- It is a precursor for most of steroid hormones 3- Some vitamins are originated from cholesterol 4- Bile acids (bile salts) are derived from cholesterol )زبدة الفقرة :الكول سترول مهم لجسم االنسان وتم ذكر جزء من أهم ته ف االربع نقاط الماض ة ولكن جب أن كون ضمن معدالته الطب ع ة الن ز ادته تؤدي لبعض األضرار( (4:20 :5:5min) In just a moment we are going to see how cholesterol is synthesized but before that let us see the structure of it: Page 1

3 Note: you are not supposed to memorize the structure but doctor want from you to know how this structure (cholesterol) was formed. What is the building block for cholesterol? Acytel CoA, and we get it from : 1- Beta oxidation of fatty acids 2- Oxidation of pyruvate that (pyruvate عائدة عال that) could come from oxidation of glucose or amino acids also from lactate Cholesterol is composed from a fused rings and side chains with methyl groups and it is amphipathic molecule, it has a polar head and non polar tail it has one hydroxyl group and it has fused rings as you can see in the figure in the previous page. Page 2

4 ( :5:5-10:04min) cholesterol synthesis starts from two acetyl CoA, each acetyl CoA is composed of 2 carbon atoms,so 2 acetyl CoA will form compound that is composed of 4 carbon atoms which are the acetoacetyl-coa, addition of another molecule of acetyl CoA to the acetoacetyl-coa then you will have a compound that is composed of 6 carbon atoms that is called HMG-CoA, the 6 carbon compound (HMG-CoA) will be converted to another 6 carbon compound called mevalonate by an enzyme called HMG-CoA reductase, mevalonate is very important because is going to be use to form cholesterol,,, you must remember the enzyme that converts HMG-CoA to mevalonate this )متوقع انه ج هاالنز م باالمتحان وهللا أعلم) enzyme called HMG-CoA reductase HMG-CoA reductase is a regulatory enzyme for the synthesis of cholesterol, it is inhibited by feedback inhibition by the final product in the pathway which is cholesterol, so the presence of high amount of cholesterol will inhibit this enzyme (HMG-CoA reductase) that catalyze the first two three steps. Page 3

5 As you will see in a moments, in order to synthesize cholesterol you have to spend a lot of ATP molecules and this is very costing to the cell, so it is physiologically important that this enzyme is inhibited in the beginning steps in order to save high amounts of ATP that are going to be used for the synthesis of a product that the cell does not need at that time. Another important thing about this enzyme (HMG-CoA reductase) that it is a target for management of the concentration of the cholesterol in the body, a lot of drugs using this biochemical strategy to be designed to inhibit this enzyme. (10:04-13:35min) STATIN : a group of drugs that are used for treatment of hypercholesterolemia in people that have high cholesterol. How these drugs act? They are competitive inhibitors for Beta HMG-CoA reductase and their structures resemble the structure of HMG-CoA (the substrate)because of that they act as competitive inhibitors of HMG-CoA. (note: the competitive inhibitor must resemble in structure the substrate of the enzyme that will inhibit) Mevalonate up on decarboxylation, it will be converted to compound of 5 carbon atoms called IPP and that by isomerization will be converted to DMAPP, so we have two important compounds after decarboxylation of mevalonate and requiring 2 ATP molecules. Each one of these two molecules is 5 carbon atoms. ) عن بشكل بس ط بعد عمل ة ال decarboxylation الل استهلكنا ف ها 2ATP حصلنا على IPP وبعد عمل ة isomerization حصلنا على ) DMAPP Page 4

6 (13:35-15:21min) The next step is to combine two molecules of 5 carbon atoms together to form a compound of 10 carbon atoms called geranyl pyrophosphate, IPP + DMAPP geranyl pyrophosphate the next step is the addition of another IPP to the ten carbon atoms and you will end up with a compound that is 15 carbon atoms which is called farnesyl pyrophosphate, two molecules of farnesyl pyrophosphate will form a compound that is 30 carbon atoms called squalene, in next step there will be cyclization and moving of some atoms to make a parent compound that resemble cholesterol which is the lanosterol. Page 5

7 (15:21-18:58min) Then, many other steps (19 steps) that will be performed on lanosterol to convert it to cholesterol. You are not supposed to memorize the 19 steps, you have to remember the geranyl,mevalonate,squalene, lanosterol, cholesterol, and the HMG-CoA reductase, how it is regulated by feedback inhibition by cholesterol and how it is in target of STATIN to decrease the concentration of cholesterol. عن كل االسماء الل انذكرت بالرسمات حفظ وتفاص ل العمل ة موجودة بالشرح بنصح انه تتابعوا الشرح مع الصور بح ث تفهموا المقصود من الكالم و ارجعوا للر كورد اذا بدكم تتأكدوا من قصد الدكتور ف الفقرة السابقة. Cholesterol is a lipid molecule and as all lipids it cannot move free in blood, so how it is transported? Page 6

8 By lipoproteins,there are many particles that are going to be formed which are composed of lipids (TG, cholesterol, phospholipids, fatty acids,cholesterol esters) that cannot be transported in aqueous media in the blood unless they are packaged with a protein to form compounds called lipoproteins. Page 7

9 And now we ll talk about lipoproteins, what are they? And what they are used for? (19:00-28:00) When we take food rich in lipids. In the intestine these lipids will pass the intestinal wall by specific mechanism and form a molecule called chylomicron to transfer these lipid via blood to the tissues. Chylomicrons are lipoproteins formed in the intestine, composed of proteins ( Apoproteins) and lipids mainly triacylglycerol (TAG) and few cholesterol, and phospholipids. and it s large in size with low density. One of the important Apoproteins that emerges from the intestine is apo-b 48 and will be linked to chylomicrons. Now the chylomicron will enter the lymphatic system and by that they bypass the liver and go to the blood directly, Page 8

10 when it s in the blood two more apoproteins will be linked to it from another lipoprotein (HDL) and they are apo-c 2 and apo-e. Chylomicrons then go to the peripheral tissue capillaries and they will block the capillaries. And there we have lipoprotein lipase that will hydrolyze the TAG to fatty acids and glycerol. here the apo-c 2 is used as a co-factor in the recognition of those chylomicrons by peripheral tissue lipoprotein lipase and it ll be removed from chylomicrons (will go back to HDL). Fatty acids will enter the tissue for storing reforming TAG (like in adipocyte), produce energy (in myocyte ), but some of these free fatty acids will go to the blood (packed with albumin) and go to other tissues, while glycerol could be used for the synthesis of glucose. Chylomicrons loses mainly it s TAG in the peripheral tissues and the cholesterol will stay the same, after the tissues take TAG from them the rest of the chylomicron is called chylomicron remnant which is smaller in size. So now we have chylomicron remnant with apo-e and apo-b 48 (apo-c 2 will be used in the recognition then it s gone), because of the apo-e it will be tracked back to the liver and it will enter the liver using LDL receptor that recognize apo-e. And this is the exogenous pathway of lipid transport via chylomicron Page 9

11 The endogenous pathway : (28:30-33:10) Page 10

12 First thing is the liver is the place that synthesis the lipoproteins in this pathway. As the liver receives signals from peripheral tissues that they need lipids (TAG,cholesterol ) the liver will start packaging those lipids and form VLDL ( very low density lipoprotein) which is rich in TAG and cholesterol and has apo-e and apo-c 2 (also from HDL) but the difference here that it has apo-b 100 and NOT B 48. Like chylomicrons these VLDL will be recognized by lipoprotein lipase in the peripheral tissue by apo-c 2 and they will hydrolyze TAG and dump them in the tissues, what remains from VLDL is a remnant that is called IDL ( intermediate density lipoprotein) which is still has apo-e and it will be tracked back to the liver, but not all of them. About 50% of IDL will be converted to LDL ( low density lipoprotein) by an enzyme called hepatic lipase (in slides) الدكتور هون حكى اسم ثان cholesterol ester transfer protein لكن هاد البروت ن وظ فته مختلفة )بعمل على تبادل الكول سترول و ال TAG ما ب ن HDL و LDL و العكس( بنتأكد من هاي المعلومة من الدكتور و بنعدلها LDL is rich in cholesterol (and that s why we call it bad cholesterol), LDL will dump some of its cholesterol in the blood vessels and this will be a building unit for atherosclerosis % of this cholesterol will go back to the liver that will recognize apo-b 100 (not apo-e) by LDL receptor on the liver. Finally we have the HDL ( high density lipoprotein) : (33:10-35:50) HDL is synthesized in liver and intestine which has very little amounts TAG and cholesterol and their function is to collect ( scavenge) cholesterol from blood vessels and the excess lipids in the tissues. One of the things that HDL does is exchanging cholesterol with TAG with LDL ( takes cholesterol from LDL and gives it TAG) decreasing cholesterol in LDL. Page 11

13 Also HDL takes cholesterol from blood vessels and exchange them with LDL.* Another HDL function is to provide specific tissues with cholesterol to synthesis hormones like testis, ovaries, adrenal It always seems impossible until it is done :) Page 12

Cholesterol metabolism. Function Biosynthesis Transport in the organism Hypercholesterolemia

Cholesterol metabolism. Function Biosynthesis Transport in the organism Hypercholesterolemia Cholesterol metabolism Function Biosynthesis Transport in the organism Hypercholesterolemia - component of all cell membranes - precursor of bile acids steroid hormones vitamin D Cholesterol Sources: dietary