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Lipoproteins and lipoprotein transport

Description

SET 1: SLIDE 19-39
sambarcelo
Mind Map by sambarcelo, updated more than 1 year ago
sambarcelo
Created by sambarcelo over 6 years ago
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Resource summary

Lipoproteins and lipoprotein transport
  1. LIPOPROTEINS

    Annotations:

    • Non-covalent lipid and protein complex:  - PL (surface) - TG (inside) - CE (some inside, most on surface) --> always transports cholesterol as cholesteryl esters - apo lipoproteins (integral)
    • Less lipid=more protein=higher density=smaller diameter=lower mass; follow order above [big to small]
    1. APOLIPOPROTEINS

      Annotations:

      • Integral proteins on lipoprotein surface that make them more soluble
      1. Apo A

        Annotations:

        • - Only on CM and HDL
        1. I

          Annotations:

          • - LCAT activator - Structure (of HDL)
          • Lecithin—cholesterol acyltransferase (LCAT) = enzyme that converts free cholesterol into CE (hydrophobic). Bound to HDLs n the blood plasma.    
          • LCAT levels affect overall lipoprotein concentration in an individual    
          1. II
            1. IV

              Annotations:

              • - LCAT activator - Satiety
            2. Apo B
              1. 48

                Annotations:

                • - Only on CM [48% of Apo B-100 is expressed from N-terminal]; upper limit to how big VLDL can be, can now be very large - Structure of CM
                1. 100

                  Annotations:

                  • - Structure - VLDL, IDL, LDL - LDLR ligand - Made in liver
                2. Apo C

                  Annotations:

                  • - Found in all types of lipoproteins EXCEPT for HDL - Accessory type
                  1. I
                    1. II

                      Annotations:

                      • Lipoprotein lipase activator
                      1. III

                        Annotations:

                        • Lipoprotein lipase inhibitor
                      2. Apo E

                        Annotations:

                        • - Found in all lipoprotein types EXCEPT for HDL - Secondary ligand for LDLR [on liver] and VLDLR [i.e. VLDL remnants]
                      3. Chylomicrons

                        Annotations:

                        • - MAJOR LIPID COMPONENT = TG
                        1. From Intestines
                          1. Travel to the lymphatic system, then the bloodsteam

                            Annotations:

                            • Goes through adipose, cardiac, and skeletal muscle tissue before returning to liver
                            1. Hydrolysis of TG by LPL

                              Annotations:

                              • LPL in peripheral tissue capillaries
                              1. CM Remnant
                                1. Hepatocyte via remnant receptor

                                  Annotations:

                                  • Contents released into cell - Packaged again into VLDL OR - Excreted [SEE BELOW FOR LIVER EXCRETION VIA BILE]
                                2. Free FAs
                                  1. Used for hepatic VLDL synthesis in liver

                                    Annotations:

                                    • Transports endogenous TG, PL, UC and CE
                                    1. ENDOGENOUS PATHWAY
                                      1. Travels in the bloodstream

                                        Annotations:

                                        • Goes through adipose, cardiac, and skeletal muscle tissue 
                                        1. Hydrolysis of TG by LPL
                                          1. VLDL remnant =
                                            1. = IDL
                                              1. Back to liver via remnant OR LDL OR APO B/E receptor
                                                1. More hydrolysis by LPL
                                                  1. LDL
                                                    1. Modification and into peripheral cells via APO B/E receptor

                                                      Annotations:

                                                      • Atheroma: accumulation of degenerative material in the inner layer of artery walls. The material consists of (mostly) macrophage cells, or debris, containing UC and FA
                                                      • Can get oxidated, more likely to accumulate in arteries
                                                      • Problem with APO B/E receptor [LDLR] on peripheral cells = FAMILIAL HYPERCHOLESTEROLEMIA
                                                      1. HDL3 via ACAT [in cell]

                                                        Annotations:

                                                        • intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol.
                                                        1. HDL2 via LCAT

                                                          Annotations:

                                                          • CM via CETP
                                                          • aka nacent HDL Nascent HDL: Obtains free cholesterol from peripheral tissues.  - LCAT promotes the uptake of free cholesterol by HDL [=esterification] - CH -> CE = hydrophobic core, higher density of  HDL  - CE transfer protein transfers CE from the HDL core and other circulating lipoproteins such as LDL.
                                                          • HDL2 <--> VLDL HDL2 <--> CM via CETP
                                                          1. CM
                                                            1. Digestion/Absorption in small intestine
                                                              1. Fecal steroids

                                                                Annotations:

                                                                • ABCG5/G8-->Similar to APCG1 but found on apical surface of the cell responsible for removal of excess cholesterol and sending it out into the lumen for excretion increase ABCG5/G8  expression(stimulated by LXR)--> more cholesterol exiting than entering cell 
                                                                1. Dietary fat, cholesterol
                                                                  1. EXOGENOUS PATHWAY
                                                                2. VLDL via CETP
                                                                  1. Taken up by liver via HDL OR LDL receptor

                                                                    Annotations:

                                                                    • SEE HOW LIVER GETS RID OF EXCESS CH BELOW Lipoprotein CH exist as CE and get degraded once inside enterocyte to contribute to UC pool [free CH pool]
                                                              2. Back to liver via LDL receptor
                                                              3. Annotations:

                                                                • Problem with LPL = Hypertriglyceridemia and the metabolic syndrome
                                                              4. Annotations:

                                                                • Problem with CD36 to take in FA from VLDL in peripheral cells = METABOLIC SYNDROME
                                                              5. Free FAs
                                                          2. Stored in peripheral tissues via CD36 receptor
                                                    2. VLDL

                                                      Annotations:

                                                      • - MAJOR LIPID COMPONENT =  TG
                                                      1. From liver
                                                      2. IDL

                                                        Annotations:

                                                        • - MAJOR LIPID COMPONENT = CE
                                                        1. From Catabolism of VLDL
                                                        2. LDL

                                                          Annotations:

                                                          • - MAJOR LIPID COMPONENT = CE - "BAD" cholesterol
                                                          1. From catabolism of IDL
                                                          2. HDL

                                                            Annotations:

                                                            • - MAJOR LIPID COMPONENT = PL - "GOOD" cholesterol [still same CH moiety as LDL]
                                                            1. From Liver and intestine
                                                            2. Can separate by charge [NOT SIZE] via agarose gel electrophoresis
                                                              1. Pre-beta mobility = VLDL

                                                                Annotations:

                                                                • Only for non-fasting individual
                                                                1. Alpha mobility = HDL

                                                                  Annotations:

                                                                  • Closest to cathode
                                                                  1. Beta mobility = LDL

                                                                    Annotations:

                                                                    • Closest to origin [=CM, no mobility]
                                                                  2. Fate of Cholesterol

                                                                    Annotations:

                                                                    • Waxy fat carried thourgh the bloodstream by lipoproteins
                                                                    1. "GOOD" = HDL

                                                                      Annotations:

                                                                      • - Stable, carries CH away form arteries - Actively soak up CH in peripheral cells, bring to liver for reuse or removal
                                                                      • - Travel in bloodstream, picking up CH [stays on outer layer - LCAT on skin of HDL, gets activated by apo A1, convert CH into CE - CE can go into HDL particle = disk becomes bigger and bigger
                                                                      1. Reverse cholesterol transport

                                                                        Annotations:

                                                                        • http://www.medscape.org/viewarticle/479499_3    
                                                                        • Some organisms can't do reverse transport due to no CETP    
                                                                        • Pathway NOT binary, can go back and forth. Depends on genotype and proteome & environment determines whether used or not.
                                                                        1. Peripheral cells

                                                                          Annotations:

                                                                          • - More interactions with ABCA1 on the surfaces of macrophages in the arterial wall, apoA-I removes excess cholesterol from these macrophages --> Free cholesterol in peripheral cell [adipose/muscle tissue] finds way to membrane, and travels to apo A1 surface= nascent pre-beta HDL, or HDL2 particles
                                                                          • Transport probably chaperoned, organizes membrane composition to allow for transport  OR can interact with apo A1 [on HDL] to create bridge
                                                                          1. HDL2 --> HDL3

                                                                            Annotations:

                                                                            • LCAT converts UC to CE [hydrophobic], so will enter the interior of the HDL2 particle = "mature" HDL [HDL3]    
                                                                            • If not converted to CE, can go back to peripheral cell membrane.    
                                                                            • HDL2 can also take CE from LDL
                                                                            • This conversion is done when there is low HDL levels in the blood
                                                                            1. LDL

                                                                              Annotations:

                                                                              • Via CETP: CE :  HDL3 --> apo B lipoproteins (remnants, VLDL, IDL, LDL via CETP) TG : apo B LP --> HDL3
                                                                              1. Liver parenchymal cells [into UC pool of membrane]

                                                                                Annotations:

                                                                                • - HDL3 is selectively taken up by the liver via SR-B1 OR - CE within apoB-containing lipoproteins is  transferred to the liver through interaction with hepatocyte LDL receptors.
                                                                                • THE ONLY ORGAN IN THE BODY THAT CAN PROCESS CHOLESTEROL FOR REMOVAL FROM THE BODY All other cells can only process small amount of cholesterol; some use more if used to make other products ex: testes, ovaries to make hormones   
                                                                                • The amount of free cholesterol is tightly controlled by the cell; maintain set point in cell membrane. If too much then several mechanisms come into play to remove extra cholesterol in the cell.    
                                                                                1. Hepatic Lipase

                                                                                  Annotations:

                                                                                  • Lipolytic enzyme, role in HDL metabolism. Partly regulates CH levels.  HL hydrolyzes TG and PL in HDL + stimulates CE uptake from HDL by hepatocytes. HL and lipid transfer proteins determine both HDL-cholesterol level and its function in reverse cholesterol transport.
                                                                                  1. Disposal of CH through bile

                                                                                    Annotations:

                                                                                    • CE from HDL3 and LDL through reverse CH transfer [now free CH in liver[ is disposed through bile
                                                                                    • 2 main pathways used by the liver to get rid of excess CH [most efficient]    
                                                                                    1. Bile Acids

                                                                                      Annotations:

                                                                                      • - Involves Cyp7a1 [RL enzyme] - UC used to synthesize bile acid cannot go back into cycle [i.e. cannot revert back to CH] - Goes to gallbladder for storage [to emulsify dietary lipids in small intestine]    - Alsoacts as signlaing molecules
                                                                                      1. Recapturing by liver from blood for reuse

                                                                                        Annotations:

                                                                                        • Can't metabolize CH and reinvest energy used, converting costs MORE energy Acetyl coA -> BA = lots of ATP so body recaptures BA and brings back to liver for usage again 3+ times more    
                                                                                      2. Biliary CH

                                                                                        Annotations:

                                                                                        • - Looks just like dietary cholesterol/lipid SO can go back into liver - Used to collect things not wanted in body - Also released into lumen of small intestine to emulsify dietary lipids [signaled by cholecystokinin in SI]      
                                                                                      3. Storage as CE in lipid droplets

                                                                                        Annotations:

                                                                                        • Only way peripheral cells can get rid of excess cholesterol BUT only small role in liver cells [have other more efficient ways]    
                                                                                        1. Lipoprotein assembly = VLDL

                                                                                          Annotations:

                                                                                          • Once too much CE stored in lipid droplets, used to make VLDL [high in CE]
                                                                                        1. Excess HDL can transfer CE to VLDL in exchange for TG via CETP
                                                                                      4. Apo A1

                                                                                        Annotations:

                                                                                        • - ApoA-I is synthesized by the liver, interacts with ABCA1 in the hepatocyte - Secreted into the plasma as a lipid-poor particle and travel to peripheral cells
                                                                                        • Problem with ABCA1 transporter in peripheral cells giving away TG to go from HDL2 to HDL3 = TANGIER DISEASE
                                                                                    2. "BAD" = LDL

                                                                                      Annotations:

                                                                                      • - Atherogenic - Sticks to artery walls and contributes to plaque build up - Also accumulates in peripheral cells like smooth muscle - Carry the majority of the CH in the blood, supplying cells - LDL receptors in peripheral cells or liver bind with LDL and clear it from the blood - Peripheral cells utilize LDL cholesterol for cell membrane structure and the production of hormones
                                                                                      • Excess CH in peripheral cells due to oxidized LDL, more likely to be deposited into the artery wall. Attract macrophages that eventually cannot handle too much free UC and die = plaque 
                                                                                    3. Binding of CM and LpL to GPIHBP1 at the Endothelial Cell Surface

                                                                                      Annotations:

                                                                                      • - CM and LPL bind to opposite acidic domain of GPI anchors [adjacent] - Brought closer together, domains interwine and CM degradation by LPL = free FA - FA goes into the cell via albumin
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