CHOLESTEROL HOMEOSTASIS

CHOLESTEROL HOMEOSTASIS

1. CHOLESTEROL

   • indispensable lipid for human life
     • steroid lipid derived from sterane, consisting of four fused carbocycles
   • where can it be found?
     • Cell membranes
       • maintenance of fluidity
       • protein interactions
     • plasma
     • tissues
   • physiological processes
     • elaboration of molecules
       • hormones, bile acids, vitamin D
     • physiopathological processes
       • large amounts of cholesterol in the blood
         • atheroma plate - arteriosclerosis
           • hardening or narrowing of the arterial light
             • cholesterol deposits on its walls
       • lipid deposits on blood vessels

2. BIOSYNTHESIS

   • DE NOVO
   • occurs in the liver
   • 2 Acetyl - CoA
     • acetoacetyl CoA
       • 3 HMG CoA
         • Acetyl - CoA
         • mevalonate
           • farnesyl pyrophosphate
             • used to synthesize CoQ
             • squalene
               • lanosterol
                 • cholesterol
                   • molecule with 27 carbon atoms
                 • complex processes
                   • three methyl groups are eliminated
                   • double bond is strengthened
                   • double bond is isomerized
             • squalene hypoxidase
         • HMG CoA reductase
           • NADPH to NADP
           • regulator of cholesterol synthesis
           • stimulated by insulin
             • inhibited by glucagon
       • HMG CoA synthase
     • acetoacetyl CoA thiolase

3. REGULATION

   • HMG CoA Reductasa
     • STEROL-DEPENDENT REGULATION
       • cholesterol in the hepatocytes
         • low concentrations
           • proteolytic cleavage of the transcriptional factor is stimulated
             • SREBP (sterol-binding protein)
               • on the cytosolic side of the membrane
               • transcriptional factor leaves the reticulum
                 • becomes activated and travels to the nucleus of the cell
                   • it bonds with a section of DNA
                     • section: STR (sterol regulator element)
                     • regulates mRNA expression in charge of encoding for HMG CoA reductase
                       • mRNA leaves the nucleus and goes to ribosomes
                         • HMG CoA reductase is synthesized
                           • more enzyme to create cholesterol
                             • increase in the amount of lipid in the cell
             • endoplasmic reticulum membrane
         • high concentrations
           • negative feedback loop
           • intermediaries in the pathway of cholesterol biosynthesis
             • cholesterol
               • return and inhibit the proteolytic cleavage of SREPB
                 • less enzyme to create cholesterol
                   • decrease in the amount of lipid in the cell
     • major control site of cholesterol synthesis
   • STEROL-INDEPENDENT REGULATION
     • HMG CoA reductase works effectively without modifications
     • HMG CoA reducatase is modified by phosphorilation
       • efectivity is decreased
         • becomes inactivated
     • ATP in hepatocytes
       • enough ATP
         • enough energy to correctly synthesize cholesterol
           • dephosphorylation of HMG CoA reductase enzyme
             • stimulated by phosphatase enzymes
               • activation of MHG CoA reductase
                 • cholesterol production does occur
       • not enough
         • the few amounts of ATP will all be converted to AMP
           • AMP binds with certain protein kinases and activates them
             • phosphorylation of HMG CoA reductase and its inactivation is triggered
               • cholesterol production does not occur
   • HORMONAL REGULATION
     • DIET - FOOD
       • after eating
         • diet with proteins, fats and carbohydrates
         • insulin is released
           • stimulation to absorb glucose from the plasma
           • beta cells of the islets of Langerhans
           • in the liver
             • regulation of the expresion of HMG CoA reducatse
               • cells are able to produce more cholesterol
                 • absorption of diet fats by means of lipoproteins
                   • cholesterol as an important component of lipiproteins
       • fed state
         • glucagon is released
           • response to low blood sugar levels
             • suppression of the expression of HMG CoA reductase
               • decrease in cholesterol production
           • alpha cells of the islets of Langerhans
   • WHAT HAPPENS WHEN THERE ARE PROBLEMS?
     • pathologies
       • Coronary heart diseases
         • cholesterol levels are too high
           • accumulation on the walls of the arteries
             • arteriosclerosis
       • strokes
         • arteries that go to the brain are narrowed and blocked
           • blood flow is interrupted
       • peripheral vascular diseases
         • neurovascular accidents
           • high blood pressure
             • diabetes

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