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Lipoproteins and Lipid Transport

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Cholesterol Synthesis

  • cholesterol only comes from animal products

  • humans can survive on cholesterol-free diet (ex. vegan) because our body can synthesize cholesterol using acetyl-CoA

    • in the cytoplasm and ER of all cells with a nucleus​

    • major tissues/organs: liver, intestine

    • mevalonate and squalene are important intermediates

  • LDL receptor mediates cholesterol uptake in cells

CHL Synthesis - Regulation

  • cholesterol biosynthetic pathway (HMG CoA synthase and HMG CoA reductase) is regulated at the transcriptional level (HMG: 3-hydroxy-3-methylglutaryl-coenzyme A)

    • cholesterol is an end product feedback inhibitor (negative feedback) when [CHL] is high​​

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  • HMG CoA reductase is the primary target

    • statins (ex. lipitor) inhibit (competetive)​

    • CHL --> faster degredation of HMG CoA reductase

    • phosphorylation --> less active enzyme

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  • 3 Acetyl CoA --------> HMG CoA --> mevalonate

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Apolipoproteins (Apo)

  • protein component of lipoproteins

  • different apolipoproteins give lipoproteins their identity

  • letters A to E used 

    • some exceptions ex. ApoB-48​

FUNCTIONS

  • stabilize lipoproteins

  • serve as markers to be recognized

    • give lipoproteins their "identity"​

  • affect enzyme activity

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Major Lipases

LIPOPROTEIN LIPASE

  • TAG --> 3 FFA + glycerol

  • works on TAGs from chylomicrons and VLDL (endogenous)

  • in capillary wall near tissue

PANCREATIC LIPASE

  • TAG --> 2 FFA + MAG

  • works on TAGs you just ate

  • pancreas --> lumen of GI

Transport of Lipids

Chylomicrons deliver TAG from GI to adipose and muscle

  • ApoB-48​

  • TAGs don't enter tissues​​​

  • TAGs are hydrolyzed first to glycerol and FFAs by an enzyme called lipoprotein lipase (LPL)

    • LPL is bound to inside of capillary walls​

    • is a glycoprotein

    • gene present in muscle, adipose and heart

    • activated by apoC II

    • LPL in adipose tissue is insulin sensitive

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Chylomicrons deliver TAG from GI to adipose and muscle

  • glycerol stays in the blood

  • FFAs enter cells

  • inside cells they are reincorporated into TAGs

    • they new glycerol for TAG synthesis comes from glucose in the cell​

  • in adipose tissue, TAGs can also be made from FFA that the adipose tissues synthesizes

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  • Dietary TAGs in chylomicrons are not the only source of TAGs

  • after a meal (high in CHO therefore excess energy) and during all 24 hours of the day, the liver synthesizes FA and forms TAGs from glucose

  • Liver does not store TAG but exports as VLDL

    • released to systemic blood to peripheral tissues​

    • if TAG accumulates in blood, it leads to fatty liver disease

    • therefore, adipose tissue receives TAG from both chylo and VLDL

  • after chylomicrons and VLDL deliver TAG to tissues, there are  remnants with much lower TAG content 

    • chylo remnants go to liver​

    • VLDL remnants are used to make

      • IDL​

      • LDL

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Lipoproteins

Chylomicrons​​

  • transports dietary TGs from the GI to the liver, adipose tissue and muscle

  • carries dietary TGs > CE

Chylomicron remnants

  • chylomicrons after most of the TG is removed within the capillary beds of muscle and adipose tissue by the action of LPL

  • carries dietary CHL

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VLDL

  • transports mostly TGs, some CHL, from liver to periphery

  • carries endogenous TGs

IDL

  • transient; derived from VLDL in the capillaries of adipose tissue and muscle after the extraction of TGs by LPL in the capillary beds

LDL

  • derived from VLDL

  • carries endogenous CHL

HDL

  • collect free CHL from other lipoproteins and cells and sends it to liver for "reverse transport" of CHL from cells to liver

  • carries CHL

  • net effect: collect CHL from peripheral cells and other lipoproteins and send back to the liver

  • in liver, CHL is used to synthesize bile acids

  • fecal disposal of bile acids is the main route for CHL to leave our bodies

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LDL METABOLISM

  • LDL delivers CHL to tissues 

  • tissues need LDL receptors to uptake LDL

  • LDL receptors:

    • transmembrane glycoprotein​

    • interacts with apoB-100

    • internalized by endocytosis

once inside cell...

  • LDL receptors release LDL and go back to the surface of cell

  • LDL is processed in lysosome

    • AAs

    • FFA

    • free CHL

      • decreases HMG CoA reductase abundance​

      • activates ACAT --> increases CE synthesis

      • decreases LDL receptor --> decreases LDL take in

LDL + apo(a) = lipoprotein A

  • Apo (a)

    • LDL-apoB-100 linked to apo(a) via disulfide bond​

    • structure homology between apo)a) and plasminogen

    • plasminogen binds to fibrin and dissolves blood clot

    • because apo(a) has similar structure, it competes with plasminogen and competes with fibrinogen

      • risk factor for CVD

    • apo(a) is linked to apoB-100 on LDL

    • apo(a) brings CHL to site of injury

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Dietary fat and CVD

positive correlation

  • total fat

  • saturated FAs

  • CHL

  • trans fat

negative correlation

  • MUFA

  • PUFA

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Stearic acid (18:0)

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©2023 by Syracuse University Dr.Margaret Voss

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