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Lecture 14

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					      Lecture 14

Lipoprotein and Cholesterol
        Metabolism
           Delivery of Fat to Tissues
                              Insulin stimulates LPL
Chylomicrons interact
with tissues through          Also increases the supply
lipoprotein lipase (LPL)      of glycerol 3-phosphate
                              for re-esterification
LPL is on the surface of
cells
Fat in chylomicrons
hydrolysed to fatty
acids and glycerol
  Fate of FAs and Chylomicrons
• Fatty acids from chylomicron after lipolysis can be:
   – Burnt in the heart and muscle
   – Stored in WAT (hopefully not elsewhere)
       • NB. Build up of fat in the muscle in Type 2 diabetes
• FAs in WAT mainly re-esterified  FAT
   – Re-esterification needs glycerol phosphate (Glyc3P)
   – WAT cannot make Glyc3P from glycerol
   – Instead Glyc3P is made by glycolysis
• As fatty acids stripped out, chylomicron becomes smaller
   – And more cholesterol rich
       • NB. Cholesterol in lipoproteins mainly in the form of cholesterol
         esters
   – Form chylomicron remnants
            Cholesterol Ester
• Cholesterol ester is totally hydrophobic
          Liver: Import/Export Control
                               Chylomicron remnants taken
                               up by liver
                               Endocytotic process
                               Internal digestion of remnants
                               Release of cholesterol into the
                               liver




Liver assembles VLDL
from fat and cholesterol
esters
The fat could have been
made by lipogenesis
VLDL excreted into the
blood stream
   VLDL & LDL - Transport of Cholesterol




LPL in peripheral tissues works on
VLDL just as it did on chylomicrons
VLDL becomes depleted in fat
Remaining particle (LDL) relatively
cholesterol rich
Tissues take up LDL through LDL
receptor
Endocytotic process like chylomicron
remnants.
This is how cholesterol is delivered to
the tissues
                 LDL & Cholesterol
• Tissues express LDL receptors ONLY if they want
  cholesterol
• Nearly all of our cells can produce cholesterol
  themselves
   –  when cells have enough cholesterol, they will stop
     making cholesterol & stop expressing LDL receptor
• Macrophages take up LDL without control, especially if LDL is
  oxidized  produce foam cells  form plaques
• HMG-CoA reductase is the rate limiting step in making cholesterol
   – Can be inhibited by statins
Reverse Cholesterol Transport
Ways to Reduce Blood Cholesterol
• Reduce consumption of cholesterol
   – Less meat, dairy products
   – But intake of cholesterol is very small vs stores
•  reabsorption of bile salts by using resins that bind to
  bile salts
   – liver has to make more bile salts from cholesterol
• Inhibit absorption of cholesterol from gut
   – Phytosterols as competitive inhibitors?
• Inhibit cholesterol synthesis by using “statins” which
  inhibit HMG-CoA reductase
• Consume polyunsaturated fatty acids
   – high saturated fat results in  HDL and LDL
                  Cholesterol Flux
• Total cholesterol in body ~140g
• ~1g of cholesterol enters the body each day from diet
   – But only 0.5 g absorbed
• ~18g bile salts secreted into gut per day
   – and 17.5g is reabsorbed per day
   – the net loss of bile salt is very little (~0.5 g/day)
• So amount absorbed = amount lost as bile salts
   – A reduction in intake will most likely be met by an increase in
     endogeous choleseterol synthesis
• But compare the store size to the intake
   – 140 g to 0.5 g
   – vs carbohydrate for which the store size and intake are similar
     magnitude
   – vs fat – intake (100 g) < store (15,000 g)
     Importance of Cholesterol
• Cholesterol is important for:
  – Steroid hormone synthesis
  – Regulating membrane fluidity
• Membrane fluidity is important for:
  – Structural integrity
  – Receptor/enzyme activity
  Membrane with Saturated FA




• saturated  FA
  – No double bond in FA
• Membrane crystalline
Membrane with Unsaturated FA




• Unsaturated FA  Kinks
• Membrane is less crystalline, more fluid and
  more permeable
Cholesterol & Membrane Fluidity
• Cholesterol “fine tunes” membrane fluidity

				
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posted:9/24/2011
language:English
pages:14