CHOLESTEROL

CHOLESTEROL

1. Steroid-like lipid substance

   • Presence of an only hydroxyl group capable of interacting with water
     • CHOLESTEROL HOMEOSTASIS
       • SOURCES
         • Exogenous
           • Diet uptake
             • Cholesterol esterification by action of LCAT in enterocytes
               • Packed inside apolipoproteins, phospholipids and vitamins
                 • Chylomicron formation
                   • Transported by the lymphatic system to the left subclavian vein
         • Endogenous
           • Biosynthesis in the liver
             • It occurs in the endoplasmic reticulum of cells
               • Condensation of two acetyl CoA molecules
                 • Acetoacetyl-CoA formation
                   • Mediated by Cytosolic thiolase
                   • Synthesis of HMG CoA
                     • Mediated by HMG CoA synthase
                     • HMG CoA reduction by NADPH
                       • Mevalonate biosynthesis
                         • Formation of isopentenyl diphosphate
                           • Squalene condensation
                             • Lanosterol formation
                               • Mediated by squalene epoxidase
                               • Cholesterol biosynthesis
                       • Mediated by HMG CoA reductase
       • TRANSPORT
         • Need special transport mechanisms in blood and extracellular fluids
           • Lipoproteins
             • HDL
               • High Density Lipoproteins
                 • Transport cholesterol from peripheral tissues to to the liver
                   • Prevents LDL oxidation
             • LDL
               • Low Density Lipoproteins
                 • Transport cholesterol from the liver to peripheral tissues
       • REGULATION
         • HMG CoA reductase
           • Transcriptional
             • SREBP
               • Sterol Regulatory Element Binding Protein
                 • In the presence of cholesterol it is bound to SCAP and Insig-1
                 • In the absence of cholesterol Insig-1 dissociates
                   • SREBP travels to the Golgi apparatus to be cleaved by proteases
                     • Cleaved SREBP migrates to the cell nucleus to be used as a transcription factor
                       • Stimulates SRE (Sterol Regulatory Element), favoring the production of HMG CoA reductase
                         • Favoring cholesterol biosynthesis
                 • Ubiquitylation
                   • Proteosomal degradation mediated by ChREBP
               • Located in the endoplasmic reticulum
           • Post-transcriptional
             • Low ATP concentration
               • Increased AMP concentration
                 • Activation of AMP-activated protein kinase (AMPK)
                   • Phosphorylation and inactivation of HMG-CoA reductase
                     • Inhibition of cholesterol biosynthesis
           • Ubiquitylation
             • Proteosomal degradation mediated by Insig
         • LDL Receptor
           • Responsible for the uptake of cholesterol from the circulation
             • Statin mediated endocytosis inhibits the uptake of cholesterol in peripheral cells
               • Causing hypercholesterolemia
         • LXR
           • HDL synthesis increase
             • Enhances reverse cholesterol transport
           • LDL synthesis decrease
     • Free
       • Slightly polar
     • Esterified
       • Non-polar
       • By the action of lecithin-cholesterol acyltransferase (LCAT)

2. Functions

   • Structural
     • It is part of the plasma membranes of eukaryotic cells
       • Lipid rafts
         • Decrease of membrane fluidity
         • Regulation of neurotransmission and protein trafficking
   • Vitamin D Precursor
   • Bile Salt Precursor
   • Hormone Precursor
     • Synthesis of progesterone, estrogen and testosterone
     • Synthesis of cortisol and aldosterone

3. Pathologies

   • Cardiovascular diseases
     • Atherosclerosis
       • LDL oxidation and formation of atheroma plaques in blood vessels

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