CHOLESTEROL

CHOLESTEROL

1. It is a lipid essential componente esencial as a component of cellular membranes, bile acids, as a precursor of steroid homones synthesis and Vitamin D

   • It is an amphipathic molecule which has a hydrophobic hydrocarbon body and a hydrophilic hydroxyl headgroup
     • Accurate levels
       • They are accepted as normal levels of 200 mg/dL plasma cholesterol maximun
         • However, it is better to start a control from 180 mg/dL to avoid in an easier way several diseases
           • If a patient has more tan 400 mg/dL in its cholesterol levels it may indicate problems in the enzyme HMG-CoA Reductase
     • Associated diseases
       • Atherosclerosis
         • This is caused when there is a lot of cholesterol (specially in LDL) and the lipoproteins oxydate in the endothelium of blood vessels. LDL competes with plasmin so fibrinolysis decreases, so when the atherosclerotic plaque breaks the thrombus can not be destroy; that is why vasoconstriction and isquemic processes appear
       • Familial hypercholesterolemia
         • it is a congenit disease that icreases the probabilty of suffering cardiovascular problems. This is caused due to a deffect gene that is in charge of the elimination of LDL
       • Dyslipidemia
         • It is one of the main death causes because of cardiovascular problems
           • Deffects in LDLR that does not let the entry of LDL and the liver does not dect cholesterol, so it synthesized more. or problems in the APo-E of the LDL necessary to bind the receptor
           • Sometimes PSK9 acts more than necessary and degradates a lor of the LDLR
     • Functions
       • To make part of PLASMA MEMBRANE, it brings rigidity, in some places it joins saturated Fatty acids forming LIPID RAFTS in which anchoring zones use to be associated
       • Synthesis of steroid hormones such as Cortisol, Aldosterone and sexual hormones (strongens, andrones and so)
       • Synthesis of Vitamin D
       • To form bile salts
       • It does not provide energy
       • To bind transmembrane proteins
     • Obtention
       • From the diet
         • Cholesteryl esters
       • Novo Synthesis
         • It is synthesized in almost of the cells of the body, however the liver is the main productor
           • Liver produces 1 g of cholesterol per day

2. Biosynthesis

   • Steps
     • Acetyl-CoA
       • Acetoacetyl-CoA
         • 3-HMG-CoA
           • Mevalonate
             • Mevalonate 5-phosphate
               • Mevalonate 5-diphosphate
                 • Mevalonate 3-phosho-5-diphosphate
                   • Isopentenyl 5-diphosphate
                     • 3,3-Dimetylallyl Diphosphate
                       • Gerenyl diphosphate
                     • Gerenyl diphosphate
                       • Farnesyl diphosphate
                         • Squalene
                           • 2,3-Oxidosqualene
                             • Lanosterol
                               • Desmoterol- 24-dehydrocholesterol
                                 • Cholesterol
                                 • Reductase
                               • Several steps
                             • Lanosterol synthase
                           • Squalene monooxigenase
                         • Squalene synthase
                       • Farnesyl PP-synthase/ cis-Prenil transferase
                     • Farnesyl PP-synthase/ cis-Prenil transferase
                     • Isopentenyl diphosphate delta isomerase
                   • Mevalonate-5-diphosphate descarboxylase
                 • Diphosphomevanolante kinase
               • Phosphomevalonate kinase
             • Mevalonate Kinase
           • HMG-CoA reductase
         • HMG-CoA Synthase
       • Thiolase (ACAT)
   • Its synthesis can be summarizedin 5 steps
     • Synthesis of MEVALONATE from ACETYL-CoA
       • Synthesis of ISOPRENOIDS adding more carbon atoms. They can derivate as substrtaes for other processes
         • Synthesis of SQUALENE fron the condensation of 6 ISOPRENOID units
           • Synthesis of LANOSTEROL (mother of steroids) from the cyclation of SQUALENE
             • Synthesis of CHOLESTEROL
   • Key facts
     • HMG-CoA reductase is probably the most important enzyme for the regulation of the biosynthesis, that is why is a target of statins (like Lovastatin)
       • HMG-CoA is stimulated at night, that the reason why statins drugs must be took at night
         • Isoprenoids can be used as substrates of different processes. For example Geranyl diphosphate is necessary on proteins prenilation.Farnesyl diphosphate produces ubiquinone, necessary for the correct function of the electrons transport chain and ATP synthesis
           • Vitamin B3 is necessary for cholesterol biosynthesis due to the high requirments od NADP reduced (NADPH) in various steps
             • Acetyl-CoA comes from pyruvate oxydation, it is important too for starting TCA cycle. When there sis enough energy in the body (ATP) most of the Acetyl-CoA is used to synthesized lipids

3. Homeostasis

   • Factors that increase its concentration (free cholesterol)
     • Novo biosynthesis
     • Hydrolysis of cholesterol esters
     • Cholesterol intake from food
     • LDL catchment mediated by LDL receptors (LDLR)
   • Factors that decrease its concentration (free cholesterol)
     • Inhibition of its novo synthesis, specially inhibition of HMG-CoA Reductase
     • Negative regulation of LDLR
     • Cholesterol esterification
     • Catchment of cholesterol of HDL from pheripheral cells
     • Conversion of cholesterol to bile acids
     • Conversion of cholesterol into steroid hormones
   • There is a protein and two enzymes that are very regulated to have a control on cholesterol biosynthesis
     • SREBP2
       • It regulates and performed, in a selectively way, some genes involucrated with enzymes that participate in the biosynthesis of cholesterol and sterols regulator. It is located in ER and it has to go to the Golgi tu interact with its nucleus. The exit of SREBP2 is regulated by the cholesterol concentration
     • HMG-CoA reductase
       • In the liver, HMGCR is phosphorylated primarily by AMPK 82, which blocks cholesterol biosynthesis when intracellular ATP levels are low. It is also inhibited by mevalonate (when there is enough) and hormones like glucagon and glucocorticoids
     • Squalene monooxygenase
       • Besides MHG-CoA reductase, this enzyme also regulates the reaction speed and the biosynthesis of cholesterol per se. When there is a lot of cholesterol, it stimulates the degradation of the squalene monooxygenase enzyme

4. Transport and absorption

   • Both processes are very important for the regulation of cholesterol and its arrive to the liver and later redistribution
     • After ingestion
       • In the apical surface of enterocytes we can find NPC1L1 (Newman Pick protein), it lets cholesterol catchment by endocytosis mediated by clathrin
         • Inside the cell, cholesterol joins phospholipids, fat acids and apolipoproteins to form a CHYLOMICRON
           • The main apoprotein of the chylomicron is apo-B48 because it lets it to go into the blood stream
             • Inside blood vessels, lipoprotein lipase (LPL) remove from the chylomicron TG (with a hydrolysis generating FA and glycerol to enter them to the cells)
               • After the action of LPL, they are Remnant chylomicrons (with high cholesterol and low TG composition)
                 • The the remnant chylomicron goes to the liver and intereacts with the LRP1 using its apoE. That is a way in which exogen cholesterol enters into the liver
     • Reverse transport
       • That the way the body eliminates the excess of cholesterol in peripheral tissues or when the extraction of it when the liver needs it. Then it will be distributed to some peripheral tissues or sxtredes in the billiary vesicle
         • First high density lipoprotein (HDL) is synthesized in the liver (or gut) and it goes to peripheral tissues
           • There, ABGC1 transporter and LCAT enzyme put into the HDL cholesterol
             • Then HDL goes to the liver and interacts with SRB1 to give its cholesterol. This is the direct way to deliver the cholesterol
               • The other way (indirect) is possible when HDL give cholesterol to Apo-B100 of LDL (changing it for TG, mediated by the CETP enzyme and them LDL interact with LDLR, as mentioned before
     • Cholesterol deliver
       • Cholesterol inside the liver (from novo synthesis) joins TG and together they form very low density lipoprotein (VLDL). It main apoprotein is Apo-B100
         • That is how liver exports cholesterol to peripheral tissues
           • Then, in the blood stream, LPL takes away the TG and some cholesterol. It turns a intermediate density lipoprotein (IDL)
             • Then the hapatic lipase (HL) removes mores TG-FA , turning it into low density lipoprotein (LDL), with with cholesterol percent of the composition
               • LDL can be oxidized in the endothelium of blood vessels and form atherosclerotic plaques
                 • LDL are the way in which the liver finds out how much cholesterol is present in the body. They bind LDLR (there is LDLR in peripheral tissues too)
                   • If there are low concentrations of cholesterol in LDL, synthesis is stimulated

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