Dyslipidemias

Annotations:

• Abnormal lipid concentration in the blood [hyperlipidemia or hypolipidemia]    
• 3 types: 1- hypertriglyceridemia – high TG 2- hypercholesterolemia – high CH 3- combined hyperlipidemia – high TG and CH   
• Can be aquired by malnutrition – deficiency or abnormally high intake OR Genetic – mutations in genes   

1. Hypocholesterolemia
   1. Abetalipoproteinemia

      Annotations:

      • - Low to undetectable circulating chylomicrons - Malabsorption of fats and fat-soluble vitamins (e.g., vitamin A, E)
      1. Clinical features

         Annotations:

         • [1] Chronic diarrhea (steatorrhea) --> Fat not absorbed, ends up in fecal matter  
         • [2] Retinitis pigmentosa (progressive degeneration of retina, can cause vision loss) -->DUE TO VIT A DEFICIENCY
         • [3] Ataxia (loss of full control of bodily movements) --> Disturbances in nerve function = develop poor muscle coordination and difficulty with balance and movement DUE TO VIT E DEFICIENCY
         • [4] Star-shaped RBCs (acanthocytosis)    --> the formation of acanthocytes depends on alteration of the lipid composition and fluidity of the red cell membrane
      2. Dietary Management

         Annotations:

         • [1] Restriction of long-chain dietary TG (<15 g/day)  --> leads to malabsorption of fat
         • [2] Use medium chain TG as an alternate source of fat --> WHY WOULD THIS WORK? All nutrients in the body need a transporter to get into the cells. Medium TG after being degraded in lumen of small intestine, does not use same transport mechanism as long chain, can diffuse into cell for absorption.
      3. Cause: mutation in the gene for MTP (MTTP)

         Annotations:

         • MTP is essential for chylomicron assembly --> w/o MTP = no CM [Microsomal triglyceride transfer protein] WHY? Found in ER membrane, reassembles digested lipid constituents to make CM. Also, deficiency in the apo B-48, which is needed for chylomicron structure.
         1. MTP deficiency

            Annotations:

            • MTP is required to the transport of TG, CE and PC between intracellular membranes  I.E. body not able to reassemble lipid constituents into CM in the ER SO stays as FA, MG, UC, lysoPC.
            1. Accumulation of CE in enterocyte

               Annotations:

               • Can't bind to apo B in lumen of enterocyte SO cholesterol stays in cells doesn't go into bloodstream
               1. Inhibition of ACAT

                  Annotations:

                  • Due to product inhibition [lots of CE already in cell so UC stays on surface]
2. Hypercholesterolemia
   1. Familial hypercholesterolemia

      Annotations:

      • TREATMENT? HMG CoA reductase inhibitors = statin + ezetimibe
      1. 1ST Reading: Brown and Goldstein

         Annotations:

         • Discovered cell surface receptor [LDLR] for plasma cholesterol transport protein [LDL] and the mechanism through which this receptor mediates feedback control of CH synthesis    
         • FH was shown to be caused by inherited defects in the gene encoding the LDLR = distrust normal control of CH metabolism
         • Receptor mediated endocytosis: - internalization of regulatory and nutritional molecules for communication --> depends on continuous movement of membrane-embedded proteins from one cell organelle to another = receptor recycling --> mutations in LDLR in FH patients disrupt movement of receptor between organelles SO message to transport CH into cells is not being transmitted properly and CH stays in the plasma    
      2. Diagnosis

         Annotations:

         • Visualize movement of CH in lab-grown cells to know how it is managed, how genes control it
         1. Isolate fibroblasts (skin cells)
            1. Grow in culture medium with growth factors

               Annotations:

               • System that regulates cholesterol synthesis in the skin = the same as the one in the body
               • Can visualize movement of CH in lab-grown cells to know how it is managed, how genes control it         
               1. Characteristics of FH fibroblast cells
                  1. Normal state

                     Annotations:

                     • - High cellular cholesterol (as CE) concentration - High rate of cholesterol (UC) synthesis - High HMG-CoA reductase activity --> Normal cell all 3 points would be LOW   
                  2. Lipoprotein depletion

                     Annotations:

                     • - No effect on CE stores (high) - No effect on rate of UC synthesis (high) - No effect on HMG-CoA reductase activity (high) --> In normal cell, mobilization of CE stores + INCREASE UC and HMG CoA
                     • Normal fibroblasts have a way of sensing the amount of nutrients [CH] in the environment (outside the cell) BUT FH fibroblasts somehow lost capacity  --> don't recognize that cholesterol in the environment is gone    
                  3. Lipoprotein addition

                     Annotations:

                     • Add LP in serum to culture as growth factor to cells [make membrane]
                     • - No effect on CE stores (high) - No effect on rate of UC synthesis (high) - No effect on HMG-CoA reductase activity (high) --> In normal cell, slight increase in cellular CE concentration and DECREASE in effect on UC and HMG CoA     
                  4. FH cells are unable to bind, internalize or metabolize LDL

                     Annotations:

                     • - No to very little binding - Some non specific binding of  LDL is able to go into cell [internalized] - Little Apo B during hydrolysis [should be high] - Rate of CH synthesis always high [should decrease] - CE levels remain very low [should increase as UC decreases] - CH esterification remains low [should increase as UC becomes CE]    
                  5. HMG CoA activity

                     Annotations:

                     • HMG CoA reductase activity remains high, regardless of any addition of LDL in serum --> In normal cells, Increasing concentration of LDL = inhibition of HMG CoA activity for normal cells   
                     • Proof that HMG CoA activity remains high: FH cells have defect in gene encoding for HMG CoA reductase = enzyme is resistant to feedback regulation by LDL-derived cholesterol. Derive from ability to extract CH from lipoprotein.    
         2. Isolate lipoproteins from blood
            1. Fractionate by density

               Annotations:

               • To characterize what kind of lipoproteins are there, which ones are carrying cholesterol    
            2. Addition of radioactive tracers

               Annotations:

               • Label apolipoprotein with radioactive tracer (such as I125 on LDL) to see the LPs and track their pathway/metabolism OUTSIDE OF LP
               • Lipids can also be labeled with radioactive tracers (such as H3 - tridium)  May be placed on the fatty acyl chains, the cholesterol moiety, etc.    INSIDE OF LP
               • WAY TO BE ABLE TO MEASURE CHOLESTEROL SYNTHESIS: Give radioactive acetate [precursor for cholesterol] to see appearance of radioactive cholesterol   
      3. Clinical Features

         Annotations:

         • [1] High concentration of cholesterol in the blood Even when fasting state, plasma is very milky due to high amount of CE [should be clear, bit of lipids]  --> WHY? Because LDLR not functioning properly, doesn't bind to LDL, which stays in the bloodstream instead of entering the enterocyte and expelling contents
         • [2] Presence of  - xanthelasmas: CH deposits in the eyelids]  - tendon xanthomas: CH deposits in the Achilles tendon, hands, feet, elbows and knees    
      4. Cause

         Annotations:

         • Absence of LDLR function    
         1. LDLR gene mutations

            Annotations:

            • Variations in gene that cause inactivation of LDL processing.     
            1. Class I

               Annotations:

               • No receptors are synthesized. Most common. No LDLR or only trace amounts.    
            2. Class 2

               Annotations:

               • Receptor is synthesized but transported slowly from ER to Golgi. Receptors are mutant precursors to normal LDLR [carbs don't get processed]; get degraded in ER or travel to surface very slowly.    
            3. Class 3

               Annotations:

               • Receptors are processed and reach cell surface, but fail to bind LDL normally. Reduced ability to bind LDL, may involve AA subs, deletions, etc.    
            4. Class 4

               Annotations:

               • Receptors reach cell surface and bind LDL, but fail to cluster in coated pits due to alterations in cytoplasmic tail of receptor. Pits needed for receptor-mediated endocytosis.    
            5. LDL receptor is a multi-domain protein
3. Inborn errors of metabolism
   1. Impact of epigenetics on genome

      Annotations:

      • Chemical modifications on the gene due to external factors that will determine accessibility of TFs to genes --> controls level of compaction of chromatin --> loose = expressed VS tight = not expressed
      • Examples [gene off]: [1] DNA methylation [2] RNA-based mechanisms --> can be silenced and not be translated by siRNA [3] Histone post-translational modifications --> can be more tightly wound
      • Even though gene may be normal, epigenetic modifications can inactivated them and still cause disease due to innacessibility
   2. Impact of regulatory elements on genome

      Annotations:

      • Most of the genome is composed of regulatory elements: [1] Long-range RE = enhancers, repressors/silencers, insulators  [2] Cis RE = promoters, TF binding sites   
      • Does not encode proteins. Modifications to these RE = impact on function of gene ex: modified binding site = unexpressed gene