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Lipid Metabolism

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					Lipid Metabolism I
            Lipids

Biological molecules soluble in
   organic solvents but only
  sparingly soluble in water.
Energy Content of Food
     Constituents
Major Classes of Lipids

 • Fatty Acids
 • Triacylglycerols
 • Glycerophospholipids
 • Sphingolipids
 • Cholesterol
                Fatty Acids




• Amphiphilic
• Usually esterified form in nature
• Saturated and unsaturated
• Usually even number of carbon atoms
     Fatty
     Acids
(cis double bonds)
               Triacylglycerols
• Constitute ~90% of Dietary Lipid
• Major form of Metabolic Energy Storage in Humans
 Importance of Triacylglycerols
     (Adipocytes and Adipose Tissue)



• Energy Resevoirs
  – Less oxidized than carbohydrates and
    protein amino acids
  – Anhydrous versus hydrated glycogen
• Thermal Insulation
Glycerophospholipids
               Glycerol




Formation from slightly modified glycolytic
             intermediates.
Phosphatidic Acid
(1,2-diacylglycerol-3-P)
Glycerophospholipid Alcohols
Sphingolipids
 (Sphingosine)
    Sphingolipids
      (Ceremides)




Precursor of Sphingolipids
       Sphingolipids
        (Sphingomyelin)




Myelin Sheath – defective in some
       metabolic diseases
  Sphingolipids
   (Cerebrosides)




Non-ionic Membrane Lipid
Sphingolipids
 (Gangliosides)
    Importance of Gangliosides

• Cell Surface Receptors
  – Hormones
  – Toxins
• Determinants of Cell-Cell Recognition
• Disorders of Ganglioside Breakdown
  – Tay-Sachs disease – fatal neurological
    breakdown
Cholesterol
    Importance of Cholesterol


• Major Component of Animal Plasma
  Membranes (and to a lesser extent
  organelle membranes)
• Precursor of Steroid Hormones
Lipid Digestion, Absorption,
       and Transport
Triacylglycerols
    The Metabolic Problem

Triacylglycerols are water insoluble
    Enzymes are water soluble
  The Metabolic Solution

Triacylglycerol digestion takes
place at lipid-water interfaces
Increasing Lipid-Water Interfaces


  Churning peristaltic movements of
            the intestine
    Emulsifying action of bile salts
     (derived from cholesterol)
              Bile Salts




Figure 20-1
      Lipases

Act at the Lipid-Water
      Interface
Pancreatic Lipase
(Triacylglycerol Lipase)
                 Colipase

• Forms 1:1 complex with triacylglycerol
  lipase in the presence of mixed micelles
• Aids in adsorption of enzyme to emulsified
  oil droplets
• Stabilizes enzyme in active conformation
Interfacial Activation of
 Triacylglycerol Lipase
Interfacial Activation of
 Triacylglycerol Lipase
  Pancreatic Lipase
  (Triacylglycerol Lipase)

Mechanism of Catalysis

   Catalytic Triad
    (Serine Proteases)
Glycerophospholipids
Pancreatic Phospholipase A2




                    [Powerful Detergent]
Substrate Binding to
  Phospholipase A2
Substrate Binding to
  Phospholipase A2




                 Hydrophobic Channel
               No Solvation/Desolvation
                     of Substrate
Active Site of Phospholipase A2
Catalytic Mechanism of
   Phospholipase A2
Catalytic Mechanism of
   Phospholipase A2
                      Oxyanion
                 Transition State
Catalytic Mechanism of
   Phospholipase A2
Pancreatic Phospholipase A2
     Bile Salts Facilitate the
  Intestinal Absorption of Lipids

• Bile salt micelles take-up nonpolar
  lipid degradation products
• Micelles move
  – across unstirred aqueous boundary layer
    of intestinal wall
  – fuse and release contents into intestinal
    cells
            Steatorrhea

       Obstructed Bile Ducts

Hydrolyzed Lipids Excreted in Feces

 Demonstrates role of bile acids in both

              lipid digestion
                    and
  absorption of lipid digestion products
   Intestinal Fatty-Acid
  Binding Protein (I–FABP)
       (cytoplasmic protein)



Increases effective solubility of
water-insoluble molecules

Protects cells from detergent-like
effects of lipids
Rat Intestinal Fatty Acid-Binding
   Protein/Palmitate Complex



                           b-Clam
             Intestinal Cells



Lipid Digestion Products ——> Triacylglycerols
Lipids (Triacylglycerols) are
Transported as Lipoproteins
            (Complexes)



Intestinal Mucosa (Exogenous Lipids)
            Chylomicrons

    Liver (Endogenous Lipids)
VLDL (very low density lipoproteins)
       Lipoproteins
  Structure and Function

Non-covalent assemblies of lipids
and proteins

Function as transport vehicles for
triacylglycerols and cholesterol in
the blood
            Classes of Lipoproteins

•   Chylomicrons: transport exogenous triacylglycerols
    and cholesterol from intestines to tissues

•   VLDL (very low density lipoproteins, IDL
    (intermediate density lipoproteins), and LDL (low
    density lipoproteins): transport endogenous
    triacylglycerols and cholesterol from the liver to the
    tissues

•   HDL (high density lipoproteins) transport endogenous
    cholesterol from the tissues to the liver
             Composition of Lipoproteins




Table 20-1
              Structure of Lipoproteins




Figure 20-5
                 Plasma Triacylglycerol and
              Cholesterol Transport in Humans




Figure 20-7
        Lipoprotein Metabolism
• Chylomicrons deliver triacylglycerols to the muscle
  and adipose tissue and dietary cholesterol to the
  liver (chylomicron remnants)
• Chylomicrons are delipidated in the capillaries of
  peripheral tissues (Lipoprotein Lipase)
• VLDL are degraded much like chylomicrons
• Cells take up cholesterol through receptor-
  mediated endocytosis of LDL
• HDL transports excess cholesterol from the
  tissues to the liver
          Lipoprotein Lipase




Partial Digestion ——> Monoacylglycerol + 2 FAs
Receptor-Mediated Endocytosis of LDL
        Receptor-Mediated Endocytosis of LDL




Figure 20-8
Conversion of Glycerol to DHAP
        (Liver or Kidney)
             HDL

Transports Cholesterol from the
      Tissues to the Liver

   Scavenger of Cholesterol
                 HDL Action

• Extraction of cholesterol from cell-surface
  membranes
• Conversion to cholesterol esters (lecithin-
  cholesterol acyltransferase, LCAT)
• SR-BI (scavenger receptor class B type I)
  – Transfer lipids to liver cell
  – Release delipidated HDL particle
   Plasma Triacylglycerol and
Cholesterol Transport in Humans
Mobilization of Triacylglycerols

         Adipose Tissue
 Mobilization of Triacylglycerols
            (Adipose Tissue)


• Hormone-Sensitive Triacylglycerol
 Lipase
• Release of Fatty Acids into the Blood

• Transport of Fatty Acids as Complex
  with Serum Albumin
Triacylglycerol Lipase
Serum Albumin Complexed with
      Seven Palmitates
  Lipoprotein Dysfunction in
Atherosclerosis and Alzheimer’s
           Disease

Deficient LDL Receptors Result in
Atherosclerosis

ApoE4 Is Implicated in Both
Cardiovascular Disease and Alzheimer’s
Disease

				
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