Lipoproteins and lipoprotein transport

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
    2. II
    3. 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
    2. 100
      Annotations:
      - - Structure - VLDL, IDL, LDL - LDLR ligand - Made in liver
  3. Apo C
    Annotations:
    - - Found in all types of lipoproteins EXCEPT for HDL - Accessory type
    1. I
    2. II
      Annotations:
      - Lipoprotein lipase activator
    3. III
      Annotations:
      - Lipoprotein lipase inhibitor
  4. Apo E
    Annotations:
    - - Found in all lipoprotein types EXCEPT for HDL - Secondary ligand for LDLR [on liver] and VLDLR [i.e. VLDL remnants]
2. Chylomicrons
  Annotations:
  - - MAJOR LIPID COMPONENT = TG
  1. From Intestines
  2. 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
        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
        Used for hepatic VLDL synthesis in liver
        Annotations:
        Transports endogenous TG, PL, UC and CE
        ENDOGENOUS PATHWAY
        Travels in the bloodstream
        Annotations:
        Goes through adipose, cardiac, and skeletal muscle tissue
        Hydrolysis of TG by LPL
        VLDL remnant =
        = IDL
        Back to liver via remnant OR LDL OR APO B/E receptor
        More hydrolysis by LPL
        LDL
        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
        HDL3 via ACAT [in cell]
        Annotations:
        intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol.
        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
        CM
        Digestion/Absorption in small intestine
        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
        Dietary fat, cholesterol
        EXOGENOUS PATHWAY
        VLDL via CETP
        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]
        Back to liver via LDL receptor
        Annotations:
        Problem with LPL = Hypertriglyceridemia and the metabolic syndrome
        Annotations:
        Problem with CD36 to take in FA from VLDL in peripheral cells = METABOLIC SYNDROME
        Free FAs
        Stored in peripheral tissues via CD36 receptor
3. VLDL
  Annotations:
  - - MAJOR LIPID COMPONENT = TG
  1. From liver
4. IDL
  Annotations:
  - - MAJOR LIPID COMPONENT = CE
  1. From Catabolism of VLDL
5. LDL
  Annotations:
  - - MAJOR LIPID COMPONENT = CE - "BAD" cholesterol
  1. From catabolism of IDL
6. HDL
  Annotations:
  - - MAJOR LIPID COMPONENT = PL - "GOOD" cholesterol [still same CH moiety as LDL]
  1. From Liver and intestine
7. Can separate by charge [NOT SIZE] via agarose gel electrophoresis
  1. Pre-beta mobility = VLDL
    Annotations:
    - Only for non-fasting individual
  2. Alpha mobility = HDL
    Annotations:
    - Closest to cathode
  3. Beta mobility = LDL
    Annotations:
    - Closest to origin [=CM, no mobility]
8. 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
        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
        LDL
        Annotations:
        Via CETP: CE : HDL3 --> apo B lipoproteins (remnants, VLDL, IDL, LDL via CETP) TG : apo B LP --> HDL3
        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.
        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.
        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]
        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
        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
        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]
        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]
        Lipoprotein assembly = VLDL
        Annotations:
        Once too much CE stored in lipid droplets, used to make VLDL [high in CE]
        Excess HDL can transfer CE to VLDL in exchange for TG via CETP
      2. 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
9. 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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Lipoproteins and lipoprotein transport

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	Created by sambarcelo over 6 years ago