Cholesterol Transport and Biosynthesis Lecture 1 PDF

Aurora Killi 29.08.21 Cholesterol transport and biosynthesis Lecture 1 Biological functions of lipids: Energy storage Constituents of membranes Anchors for membrane proteins C...

Aurora Killi 29.08.21 Cholesterol transport and biosynthesis Lecture 1 Biological functions of lipids: Energy storage Constituents of membranes Anchors for membrane proteins Cofactors for enzymes Signaling molecules Pigments Detergents Transporters Antioxidants Every food that is ingested in the human body is hydrolyzed into its monomers in the small intestines, where they are absorbed Lipoproteins Lipids are non-water-soluble substances, and thus they are transported as lipoproteins so they can be transported into water filled environments like the blood and other bodily fluids. Lipoproteins are macromolecular complexes whose chore contains cholesterol, TAGs, and cholesteryl esters, which are more nonpolar than cholesterol. This core is coated surrounded by apolipoproteins and phospholipids. Classes of lipoprotein particles: Subdivision of four different classes Named based on position of sedimentation (density) in centrifuge – based on their density Composition of these particles differentiate a lot between the classes of lipoproteins Lipoproteins also transport fat-soluble vitamins such as vitamin A and E The density of lipoproteins is determined by the composition of constituents. TAGs are the ones that physically takes up more fat space, because their fatty acid tails are quite loose in their structure. Thus, their density is lower, and their size is bigger. This can be seen in the electron microscope pictures of the various lipoproteins. 1  Aurora Killi 29.08.21 Apolipoproteins Refers to the protein part of a lipoprotein molecule Their primary role is to ensure the transport of various lipids between organs, because these apolipoproteins can serve as ligands for receptors and can activate/inactivate lipoproteins lipase, which is the enzyme that hydrolyzes the fats that these particles are carrying Some apolipoproteins, such as apolipoprotein B (ApoB), are embedded in the particle surface and determine the interaction with cellular receptors. Others, such as ApoC, are only loosely bound and van be exchanged between different lipoprotein classes Various apolipoproteins have been discovered, and their size varies a lot. Some of the apolipoproteins only have one corresponding lipoprotein class (e.g., ApoA-1). Whereas others are common to various classes of lipoproteins. The function of some of the apolipoproteins have not yet been discovered. 2  Aurora Killi 29.08.21 Biological role of lipoproteins in trafficking cholesterol and TAGs Each class of lipoprotein has a specific function determined by its point of synthesis, lipid composition and apolipoprotein content. Three different primary routes can be distinguished: Exogenous pathway - ensures the transport of dietary lipids from intestines to the liver Endogenous pathway - ensures the transport of lipids synthesized in the liver to the periphery Reverse cholesterol pathway - ensures the transport of excess cholesterol from the periphery back to the liver Exogenous pathway Chylomicrons in charge. Chylomicrons give plasma a milky appearance, and their half-life is less than 1 hour. 1. After chylomicrons are formed into enterocytes and released into the lymphatic system, they enter the bloodstream via the left subclavian vein. This is located right behind the bone in the neck area. 2. ApoC-II activates lipoprotein lipase in the capillaries. Especially in the capillaries of adipose, heart, skeletal muscle and lactating mammary tissues. Lipoprotein lipase starts the breakdown of the TAGs and release them in these tissues for storage, energy use or synthesis of some other lipids for milk production. Fats are the primary energy for the heart muscle. 3. When the TAGs are released in the tissues (adipose, heart, skeletal muscle and lactating mammary), the particle itself decreases in size. This particle is called a chylomicron remnant. The remnants still contain cholesterol, ApoE and ApoB-48. This remnant of the particle now travels back through the blood stream to the liver. ApoE ensures the endocytosis of these particles in the liver. 3  Aurora Killi 29.08.21 4. In the liver, remnants are broken down and release cholesterol and are further degraded in the lysosomes Endogenous pathway Very low density lipoproteins (VLDL) in charge 1. Diet that contains higher levels of cholesterol and fatty acids than needed, ensure formation of TAGs or cholesteryl esters in the liver. They are formed and packed within very low-density lipoproteins along with ApoB100, ApoC-I, ApoC-II, ApoC-III and ApoE. Also, diet that are rich in carbohydrates can lead to the same formation of very low-density lipoprotein formation. This is because oxidation of carbohydrates leads to formation of pyruvate which is converted into Acetyl-CoA. If the acetyl-CoA as energy is not needed, the body uses Acetyl-CoA to form different fats (fatty acids, cholesterol etc.). The use of the low-density lipoproteins is dependent on the state of the body - whether we have a lot of energy, or if the body needs energy. 2. a) If insulin is present – which means that we have eaten food and the body has enough energy - VLDL will primarily convey lipids from the diet to adipose tissue for storage 2. b) If glucagon is present – which means that the blood glucose levels are low and that we need energy – VLDL will primarily originate from the fats that are stored in the adipose tissue. Adipose tissue will break down TAGs to free fatty acids which will be transported to the liver where they are reformed into TAGs and packed into VLDL which can be sent out into the bloodstream and deliver it to tissues where it is needed. This is of course the muscle tissue since adipose tissue is the source of energy. 2. c) Loss of TAGs initially convert VLDL to intermediate density lipoproteins IDL (also called VLDL remnants). These intermediates are further on converted into low density lipoproteins LDL. VLDL particles that are released into the bloodstream, on their way through the circulatory system are changed into other particles of lipoproteins. This happens because when VLDL bypass the adipose they will catch up with the lipoprotein lipase that is still sitting in the capillaries, and they are going to release some of the TAGs and again getting smaller in size. Once that has happened, we are creating these intermediates lipoproteins, also called VLDL remnants. 3. Major apolipoprotein of LDL is ApoB100, and LDL primarily contains cholesteryl esters which are carried to muscle tissue, adrenal glands, and adipose tissue 4. LDL also delivers cholesterol to macrophages (immune cells), sometimes converting them into foam cells. 5. Extra LDL that is not needed in the tissues, returns to the liver and is taken up through LDL receptors through endocytosis. 4  Aurora Killi 29.08.21 Cholesterol uptake by receptor-mediated endocytosis ApoB-100 is also present in VLDL, but its receptor-binding domain is not available for binding to the LDL receptor. The conversion of VLDL into LDL exposes this part of the apolipoprotein. There is only one molecule of ApoB-100 per each lipoprotein particle, thus the measurement of the ApoB in plasma reflects the sum of the VLDL, ILD, and LDL 1. First, the cell needs receptors. The receptors are synthesized by the endoplasmic reticulum. Through the Golgi apparatus the receptors are transferred to the plasma membrane. 2. ApoB-100 binds to the LDL receptor, which will initiate the endocytosis. The whole particle is integrated into the cell (either muscle, adipose etc.) 3. LDL is internalized in endosome 4. LDL receptor is segregated into a vesicle on its own and recycled to the cell surface to be used again 5. Once the lipoprotein particle is alone in the endosome, lysosomes will fuse with it. 6. Lytic enzymes in the lysosome degrade ApoB-100 and cholesteryl esters, releasing amino acids, fatty acids, and cholesterol Reverse cholesterol transport High density lipoproteins in charge Step 1: High density lipoprotein (HDL) originates in the liver and small intestine as small, protein rich particles called nascent HDL. Nascent HDL is partly constructed from the excess phospholipids shed from the VLDL during their hydrolysis by LPL. The nascent HDL is not yet mature and cannot serve a function in the cholesterol transport. The nascent HDL released into the bloodstream, passes by the peripheral cells Step 2: In the peripheral cells, the nascent HDL picks up free cholesterol with the help of ApoA-1. ApoA-1 ensures the binding of nascent HDL to peripheral cells and cholesterol transport by activating the ABCA1 transporter. ApoA-1 ensures that the transporter ABCA1 is activated and that it helps to attach for the particle nascent HDL particle to the peripheral cells. ABCA1 uses ATP as a source of energy and thus it is the rate-limiting step for the efflux of free cholesterol to ApoA-1. Step 3: The nascent HDL contains an enzyme called Lecithin-cholesterol acyl transferase (LCAT). This enzyme ensures the esterification of the free cholesterol, which means that it adds a fatty acid to the OH group of the cholesterol, making it less water soluble than a normal cholesterol molecule. When this process 5  Aurora Killi 29.08.21 happens, the HDL molecule becomes spherical, and we can now say that it is a mature HDL molecule that ensures the reverse cholesterol transport. Step 4: The mature HDL particle can give away its cholesteryl esters to the IDL (VLDL remnant) which is further converted into LDL. Once the mature HDL lipoprotein particle is formed, then there is a cholesteryl ester transfer protein (CEPT) which can either deliver cholesteryl ester from the HDL to the IDL. But is can also simultaneously transfer triglycerides back to the mature HDL molecule. During this process the mature HDL molecule becomes bigger. This means that the HDL is not the only corresponding lipoprotein that carry the cholesterol back to the liver. Due to this exchange, also LDL can carry cholesteryl ester back to the liver. Step 5: Because of the exchange in step 4, some of the cholesteryl esters that are formed in HDL are carried to the liver by VLDL remnants and chylomicron remnants. However, the main route is that the HDL itself does travel back to the liver. Step 6: HDL itself goes to the liver, where parts of its triglycerides and phospholipids are hydrolyzed by hepatic TAG lipase (HTGL). This converts larger HDL particles called HDL-2, back to smaller HDL particles called HDL-3. Step 7: While still traveling through the liver, the HDL-3 particle encounters the Scavenger receptor B1 (bidirectional carrier). This is the receptor that transfers the corresponding cholesteryl esters into the liver cells (hepatocytes). This process is ensured bidirectionally and depleted HDL then dissociates to recirculate in the bloodstream, and in the end forms the nascent HDL. We can say that the reverse cholesterol transport involves three different routes: 1. ApoE-mediated endocytosis of remnant particles, which have obtained part of their cholesteryl esters from HDL (no. 13 in scheme) 2. Direct transfer of cholesterol esters from HDL during lipolysis by HTGL, mediated by SR-B1 (main route, no. 12 in scheme) 3. Endocytosis of large ApoE-coated HDL particles in the liver. This is a very rare route of the reverse cholesterol transport. Characteristics of lipoproteins Chylomicrons LDL Least dense of the lipoproteins because it Produced by removal of TAG from VLDL contains the most TAGs LDL is enriched in cholesterol/cholesteryl esters Have ApoB-48, ApoE, and ApoC-II ApoB-100 is the major apolipoprotein 6  Aurora Killi 29.08.21 VLDL HDL Contain TAG and cholesteryl ester in high Produced from enzymatic conversion of LDL concentration and VLDL cholesterol to cholesteryl esters Contain ApoB-100, ApoC-I, ApoC-II, ApoC-III, HDLs are high in protein, including ApoA-I and ApoE Activation and mobilization Chylomicrons LDL ApoC-II activates lipoprotein lipase to allow Muscle and adipose tissue have LDL receptors free fatty acid release for fuel in adipose tissue, and recognize ApoB-100 heart, and skeletal muscle Myocytes and adipocytes take up cholesterol When fats are depleted, the remnants go to via receptor mediated endocytosis the liver for absorption via ApoE mediated endocytosis VLDL HDL Again, ApoC-II activates lipoprotein lipase to HDL picks up cholesterol from the cells and release free fatty acids (FFAs) returns to the liver, where it can be Adipocytes take up the FFAs, reconvert them to metabolized (e.g., bile salts) TAGs, and store them in lipid droplets Also catalyzes conversion of cholesterol of Muscles use FFAs for energy VLDL and its remnants to cholesteryl esters Cholesterol It has been estimated that we use 30% of our daily cholesterol intake for cell functions Every tissue and cell in our body can synthesize cholesterol on its own. Out of all the cells, the liver is the major producer. Because our body can synthesize cholesterol on its own, it is not required from our diet. Cholesterol is a 27C complex molecule. There are four ring structures that forms the steroid structure of the cholesterol molecule. Functions Cholesterol is a part of the cell membrane which prevents solidifying of phospholipids tails, so they are not making a clot, which again o Adds firmness and integrity o Maintains fluidity and elasticity at different physiological temperatures Cholesterol in the cell membrane also helps to reduce permeability to some solutes such as o Neutral solutes o H+ o Na+ Cholesterol is a precursor for steroid hormones o Estradiol: male and female sex hormones. Influence secondary sexual characteristics, regulate female reproductive cycle o Aldosterone: regulates reabsorption of Na+, Cl-, HCO3- in the kidney o Cortisol: affects protein and carbohydrate metabolism, suppresses immune response, inflammation, and allergic responses Precursor for bile acids Precursor for vitamin D. Vitamin D is a hormone, and in addition to its role in calcium homeostasis, it influences genes involved in cell proliferation, differentiation, and apoptosis. Deficiency of vitamin D produces rickets in children and osteomalacia in adults 7  Aurora Killi 29.08.21 Cholesterol biosynthesis Place of action: every cell of the human body, but primarily in the liver. More specifically in the endoplasmic reticulum, but also in cytosol and peroxisomes Before we can start the synthesis of cholesterol, what is important to remember is where acetyl Co-A is produced, which is in the matrix of mitochondria. Whereas the biosynthesis takes place in the other cell compartment. Therefore, we need to transport Acetyl-CoA from the matrix of mitochondria into the cytosol, no matter what for we use the Acetyl-CoA. This is done by the malate-aspartate shuttle or the pyruvate transporter, and we need 1 ATP to ensure Acetyl-CoA release into the cytosol. 1. ATP if malate-aspartate shuttle is used: The first step in the citric acid cycle is to form oxaloacetate into This means that in order to citrate. After citrate is transported out of the matrix it is ensure Acetyl-CoA release in transferred into oxaloacetate. In the cytosol the reverse reaction the cytosol 1 ATP is needed. take place where citrate is transferred into oxaloacetate, and CoA is used and this process requires one ATP. To finish this shuttle some molecules have to be returned to the matrix. There are two ways this can occur. Firstly, through the malate-aspartate shuttle can malate be formed and transported back into the mitochondria in order reform oxaloacetate. 2. Pyruvate transporter can be used: Secondly, from the malate we can also form pyruvate, and through the pyruvate transporter it can be transported back into the matrix where oxaloacetate can be formed. This is one step of the gluconeogenesis. This is important since the reaction from malate to pyruvate forms NADPH, which is necessary for the fatty acids and cholesterol biosynthesis. Overview of the eukaryotic cholesterol biosynthesis 1. Three acetates condense to form 6-C mevalonate 2. Mevalonate converts to phosphorylated 5-C isoprene 3. Six isoprene’s polymerize to form the 30-C linear squalene 4. Squalene cyclizes to form the four rings that are modified to produce cholesterol 8  Aurora Killi 29.08.21 Step 1: Formation of Mevalonate from Acetyl-CoA Enzymes: (1) Thiolase, (2) HMG-CoA synthase, (3) HMG-CoA reductase Substrate: Acetyl-CoA Intermediates: Acetoacetyl-CoA, β-Hydorxy- β-metylglutaryl-CoA Product: Mevalonate ATP: 2 Acetyl-CoA per 1 Mevalonate → 2 ATPs per 1 Mevalonate 1. Takes place in cytosol and performed by the enzyme: Thiolase. Firstly, one carbon unit from one of the Acetyl-CoA is transferred to another with the help of the enzyme thiolase (also called acetylCoA acetyl transferase). This transfer then forms Acetoacetyl-CoA, which has four carbon atoms in its main structure). 1. Takes place in cytosol and performed by the enzyme: HMG-CoA synthase. Secondly another Acetyl-CoA is used by the enzyme HMG-CoA synthase and a six-carbon structures is formed called “B-Hydroxy-B-methylglutaryl- CoA” (HMG-CoA) 2. Rate limiting step, takes place in ER and performed by enzyme: HMG-CoA reductase. This is is an oxidation-reduction reaction and it is using two NADPH. Mevalonate is formed and has six carbon atoms. Step 2: Conversion of Mevalonate to activated Isoprenes in peroxisomes Enzymes: Mevalonate 5-phosphotransferase, phosphomevalonate kinase, pyrophosphomevalonate decarboxylase, pyrophosphomevalonate decarboxylase Substrate: Mevalonate Intermediates: 5-Phosphomevalonate, 5-Pyrophosphomevalonate, 3- Phospho-5-pyrophosphomevalonate Products: Isopentyl pyrophosphate, Dimethylallylpyrophosphate (active isoprenes) ATP: 3 ATPs per 1 isoprene Isoprene’s means five carbon long molecules and activated means that there are phosphor groups attached to them. The same phosphorylation is occurring five times in a row. 1. Enzyme: Mevalonate 5-phosphotransferase transfers mevalonate into 5- phosphomevalonate using 1 ATP 2. Enzyme: Phosphomevalonate kinase transfers 5-phosphomevalonate into 5- Pyrophosphomevalonate using 1 ATP 3. Enzyme: Pyrophosphate-mevalonate decarboxylase transfers 5- Pyrophosphomevalonate into 3-Phospho-5-pyrophosphomevalonate by using 1 ATP. The formation of 1 4. Enzyme: Pyrophosphate-mevalonate decarboxylase transfers 3-Phospho-5- isoprene unit needs 3 pyrophosphomevalonate into ∆3- Isopentenyl pyrophosphate. There also exists ATPs an isomer called Dimethylallyl pyrophosphate. Both these activated isoprene’s are needed to ensure biosynthesis of cholesterol. In this step both the CO2 group and carboxyl group is removed. 9  Aurora Killi 29.08.21 Step 3: Formation of Squalene in the endoplasmic reticulum Enzymes: Prenyl transferase, squalene synthase Substrate: Isopentenyl pyrophosphate, dimethylallylpyrophosphate Intermediates: Geranyl pyrophosphate, Farnesyl pyrophosphate Product: Squalene All these reactions occur in Endoplasmic reticulum. 1. Head-to-tail condensation: The two isoprene’s formed in the previous step: ∆3- Isopentenyl pyrophosphate and Dimethylallyl pyrophosphate are now condensed with head-to-tail condensation. This means that the head (phosphate part*) of ∆3- Isopentenyl pyrophosphate is released as PP, while the Dimethylallyl pyrophosphate and the tail (carbon-chain) of ∆3- Isopentenyl pyrophosphate joins together. We will then get a C10 molecule, which is named “geranyl pyrophosphate”. 2. Head-to-tail condensation: The head-to-tail condensation occurs once more, where one more ∆3- Isopentenyl pyrophosphate is added, and we formed a c15 atom called “farnesyl pyrophosphate” 3. Head-to-head condensation: Two pyrophosphate groups will be released since the head-to-head condensation occurs. We add one more farnesyl pyrophosphate to the already existing one. This results in C30. Intermediates of this step is isolated from various types of plants and animals. From that we have the name of the intermediate “Geranyl”. Squalene is isolated from sharks? Step 4: Conversion of squalene to a four-ring steroid nucleus Enzymes: Squalene, monooxygenase, cyclase Substrate: Squalene Intermediate: Lanosterol Product: Cholesterol 1. The enzyme squalene monooxygenase adds one oxygen to the end of the squalene chain which later forms the only hydroxyl group typical for the cholesterol. This oxygenation ensures rearrangement of the double bonds of the original squalene. This allows the rings in the squalene to appear. 2. Then the enzyme cyclase ensures the cyclization which allows the double bonds to form this ring structure. Finally is lanosterol created which have 30 carbon atoms in their structure. 3. 20 reactions then take place to form cholesterol from lanosterol. We are not looking into them; but the primarily thing you can notice is that there are loss and which of the double bonds and one methyl group is lost. A fully cholesterol molecule has 27 carbon atoms. ATP count in the cholesterol biosynthesis 10  Aurora Killi 29.08.21 36 18 Acetyl-CoA to make 6 mevalonate molecules. That means we need 18 ATP to transport those Acetyl- CoA inside the matrix. Then we need 18 more in step 2 of the cholesterol biosynthesis which equals 36 ATP. Cholesterol in free form is not as common as the cholesteryl esters in our body. This is because free cholesterol can easily penetrate the cell membranes and thus change the cells properties. Thus, there is an esterification of cholesterol by the attachment of fatty acid to the hydroxyl group, which prevents cholesterol from entering the cells. Usually, the cholesteryl esters that are synthesized will be packed into VLDL and transferred to the peripheral tissues or stored in the liver in form of lipid droplets until they are needed for bodily functions. Five modes of regulation of cholesterol synthesis and transport Short term 1. Covalent modification of HMG-CoA reductase (rate limiting enzyme) Long term 2. Transcriptional regulation of HMG-CoA reductase gene 3. Proteolytic degradation of HMG-CoA reductase 4. Activation of acyl-CoA-cholesterol acetyl transferase (ACAT) 5. Transcriptional regulation of the LDL receptor Regulation of cholesterol metabolism Short term Everything depends on how much energy we have, and how much energy we can invest in the synthesis of cholesterol. The biosynthesis of cholesterol can only happen when the body is in an energy rich state. The hormone that notifies the body of an energy rich state is insulin. 1. AMP-dependent protein kinase: if there is a low concentration of ATP which means that there is an increase in AMP, then AMP dependent protein kinase will be the enzyme that phosphorylates HMG-CoA reductase and thus lowers the production of cholesterol. 2. Glucagon, epinephrine: cascades lead to phosphorylation HMG-CoA which lead de decreased activity of the cholesterol biosynthesis. The opposite process of insulin. 3. Insulin: cascades will lead to dephosphorylation of HMG- CoA and thus the activity of the cholesterol biosynthesis is increased. This is because HMG-CoA reductase is most active when it is dephosphorylated. The rate limiting enzyme HMG-CoA reductase is most active when it is !dephosphorylated! Cardiovascular disease (CVD) is multifactorial 11  Aurora Killi 29.08.21 Very high LDL cholesterol (the one that travels from the liver to the periphery) levels tend to correlate with atherosclerosis. Although many heart attacks victims have normal cholesterol, and many people with high cholesterol do not have heart attacks. Total cholesterol: 3.5 - 5 mmol/L Low HDL cholesterol (the lipoprotein particles that travels «Good» cholesterol HDL: ≥ 1.8 mmol/L back to the liver for excretion from the body) levels are “Bad” cholesterol LDL: ≤ 3.5 mmol/L negatively associated with heart disease Plaque formation In addition to cholesterol, plaque formation is facilitated with low grade chronic inflammation, calcification, and fibrin. Low grade chronic inflammation is usually a result of bad lifestyle choices. In case of adiposity, the adipocytes secrete inflammatory markers that circulate in our blood stream and can cause slight microinflammation of the inner lining of the vasculature. This means that the endothelial cells are not held as tight together by the junctions in between them which leads to a greater possibility for LDL particles to sneak in-between the endothelial cells and accumulate between the outer layer of smooth muscle and endothelial cells. Usually, these LDL particles are already modified, they are so-called oxidized LDL particles, which is typically smaller in size which facilitates their accumulation and incorporation. This process causes monocytes to be sent to the site of inflammation where the oxidized LDL are attached. The monocytes differentiate into macrophages and their role is to pick up these oxidized LDL particles and to form foam cells. These foam cells and the corresponding accumulation in the area, further on stimulates an inflammation and lack of oxygen in the tissue. This will lead to apoptosis, necrosis, tissue damage and so on. On top of that, is that the smooth muscle cells are now growing on the other side of the plaque to ensure that it does not break off. Hyperlipoproteinemia Plasma lipids phenotypes Type Name Triglyceride Cholesterol Fraction Incidence Causes elevated I Hyperchylomicronemia ↑↑↑ (↑) Chylomicrons Rare Inherited deficiency of LPL or ApoC-II, systemic lupus erythematosus, unknown II Hypercholesterolemia (↑) ↑↑ LDL Common Primary: familial hypercholesterolemia Secondary: obesity, poor dietary habits, hypothyroidism, diabetes mellitus, nephrotic syndrome III Dysbetalipoproteinemia ↑ ↑ Chylomicron Rare Homozygosity for remnants, ApoE-2, combined with VLDL poor dietary habits remnants IV Hypertriglyceridemia ↑↑ ↑ VLDL Common Diabetes mellitus, obesity, alcoholism, poor dietary habits 12  Aurora Killi 29.08.21 V - ↑↑ ↑ Chylomicrons Rare Diabetes mellitus, VLDL obesity, alcoholism, oral contraceptives Familial hypercholesterolemia Most common of the inherited diseases 1. Due to genetic mutation in LDL receptor. This receptor is expressed in every cell in the human body and its role is to ensure the endocytosis of LDL particles. The cholesterol will then accumulate and form foam cells. If the cell is not able to gain the cholesterol which is transported with the LDL the cell will synthesizes on its own. Then it will be a double synthesis of cholesterol in our body. 2. Impairs receptor-mediated uptake of cholesterol from LDL 3. Cholesterol accumulates in the blood and in foam cells 4. Regulation mechanisms based on cholesterol sensing inside the cell don´t work 5. Homozygous individuals can experience severe CVD as youths 6. Symptoms: atherosclerosis, corneal arcus (highly specific if < 45 years of age), xanthelasmata (not so specific), tendon xanthoma (highly specific) Statin drugs lower cholesterol biosynthesis Statin drugs inhibit HMG-CoA reductase to lower cholesterol synthesis Statins resemble mevalonate in their structure which means that they are competitive inhibitors of HMG-CoA reductase. Statin drugs was first found in fungi which grows on trees. Extracted from these fungi it was proven that statin lowers serum cholesterol by as much as 30% in individuals with hypercholesterolemia. Also reported that the drug improved circulation, stabilized plaques by removing cholesterol from them, and reduced the vascular inflammation. These drugs have proven to be good in combination with edible resin that binds bile acids and prevents their reabsorption form the intestines. Bile acids are formed from cholesterol, and this is the only way we can get rid of cholesterol from our body. If we can prevent reabsorption of bile acid, and we would need to form new ones from our body. Cholesterol will be used for this, which reduces the cholesterol levels. Reverse cholesterol transport Reverse cholesterol transport by HDL explains why HDL is cardioprotective Tangier disease is very rare, less than 100 families worldwide with this disease is known. Lacks ABCG1 which is the transporter that is found on the peripheral cells in which free cholesterol is transferred back to the liver. HDL picks up cholesterol from non-liver tissues, including foam cells at growing plaques HDL carries cholesterol back to the liver Summary of the cholesterol transport Lipoproteins transport hydrophobic lipids between organs and tissues Chylomicrons mediate transport of dietary triacylglycerols VLDL mediate the transport of endogenously synthesized triacylglycerols Chylomicrons, VLDL, and remnants lipoproteins are a part of the organism´s fuel distribution network 13  Aurora Killi 29.08.21 LDL are cholesterol-rich lipoproteins generated from VLDL remnants. Like the remnant particles, they are small enough the enter the arterial wall and create atherosclerotic plaques. HDL mediate reverse cholesterol transport (e.g., removal of cholesterol from the peripheral cells and its transport to the liver Summary of the cholesterol biosynthesis Cholesterol is an essential constituent of cell membranes and the precursor molecule for bile acids, steroid hormones, and vitamin D Cholesterol is both supplied with the diet and synthesized de novo form acetyl-CoA in each cell of the human body The rate limiting enzyme in the cholesterol synthesis is HMG-CoA reductase Production of isoprene for cholesterol biosynthesis occurs through the mevalonate pathway and starts with 3 acetyl-CoA molecules Short term regulation is mediated with hormones like insulin, glucagon Long term regulation includes increased expression un proteolysis of HMG-CoA reductase Statins are competitive inhibitors of HMG-CoA reductase and reduce the formation of atherosclerotic plaques. 14