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VLDL formation. Apolipoprotien B-100 has a repeating - helix/ - sheet structure:. Lipids are packaged as apolipoprotein B-100 is being synthesized:. From Shelness & Sellers (2001) Curr Opin Lipidology 12:151-157. VLDL formation. VLDL stands for Very Low Density Lipoprotein

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Vldl formation
VLDL formation

Apolipoprotien B-100 has a repeating -helix/-sheet structure:

Lipids are packaged as apolipoprotein B-100 is being synthesized:

From Shelness & Sellers (2001) Curr Opin Lipidology 12:151-157


Vldl formation1
VLDL formation

  • VLDL stands for Very Low Density Lipoprotein

  • As it is synthesized, VLDL contains:

    • One molecule of apoliprotein B-100

    • Triacylglycerol

    • Phospholipid

    • Cholesterol ester

  • Microsomal Triacylglycerol Transfer Protein(MTP) assists in the formation of the VLDL

  • Other components are added to the VLDL in the blood.


  • Vldl formation2
    VLDL formation

    • Apolipoprotein B-100 synthesis is required for the transport of lipid out of the liver

      • If protein synthesis is reduced (e.g. by malnutrition) fat droplets accumulate in the liver.

      • If the rate of lipid synthesis is greatly elevated with respect to protein synthesis (e.g. in type I diabetes or glucose 6-phosphatase deficiency) fat droplets accumulate in the liver.


    Triacylglycerol oxidation
    Triacylglycerol Oxidation

    Lipases

    Triacylglycerol 3 fatty acids + glycerol

    • During starvation adipose tissue does not release triacylglycerol.

    • It releases fatty acids and glycerol (produced by adipose lipases).

    • In the fed state triacylglycerol is transported in the blood

    • as a lipoprotein complex. In the blood the triacylglycerol

    • is hydrolyzed to produce fatty acids and glycerol (lipoprotein

    • lipase or hepatic lipase).


    Triacylglycerol oxidation1
    Triacylglycerol Oxidation

    • Glycerol can be converted to glucose

      • Glycerol kinase is present in liver but not normally present in adipose

        Glycerol Glycerol-3-Phosphate DHAP

        ATP ADP + Pi NAD+ NADH + H +

    H2C-OH

    |

    O=C O

    | |

    H2C-O-P-O -

    ||

    O -

    H2C-OH

    |

    HOCH O

    | |

    H2C-O-P-O -

    ||

    O -

    H2C-OH

    |

    HOCH

    |

    H2C-OH

    Glycerol-3-phosphate

    dehydrogenase

    Glycerolkinase


    Triacylglycerol oxidation2
    Triacylglycerol Oxidation

    • Fatty acids must be activated to Acyl-CoA

      Fatty acid + CoA + ATP Acyl-CoA + AMP + PPi

      PPi + H2O 2 Pi

    Acyl-CoA synthetase

    Pyrophosphatase


    Triacylglycerol oxidation regulation
    Triacylglycerol OxidationRegulation

    • Fatty acid oxidation takes place in the mitochondria.

    • Transport into the mitochondria is the primary rate limiting step of fatty acid oxidation.

    • The maximum rate of fatty acid oxidation is transcriptionally regulated by PPARα.

      • Unsaturated fatty acids increase PPARα activity

      • Fibrates, a class of triacylglycerol lowering drugs, increase PPARα activity.

      • Note PPAR will be persented in Thursday’s lecture


    Triacylglycerol oxidation3
    Triacylglycerol Oxidation

    Inhibited by

    Malonyl-CoA

    • Carnitine Shuttle

      Acyl-CoA + Carnitine Acyl-Carnitine + CoA

    CAT-I

    CAT-II

    CAT-II

    Acyl-CoA + Carnitine Acyl-Carnitine + CoA

    Mitochondrion

    Inner membrane

    Outer membrane

    CAT - Carnitine Acyl-CoA Transferase


    Triacylglycerol oxidation4
    Triacylglycerol Oxidation

    • β-oxidation of acyl-CoA

      • Two carbons at a time are oxidized and removed as acetyl-CoA

      • For each two carbons removed, 1 FADH2 and 1 NADH + H+ are produced

      • For palmitoyl-CoA, the reaction is:

        Palmitoyl-CoA + 7FAD + 7NAD + 7CoA + 7H2O

        8Acetyl-CoA + 7FADH2 + 7NADH + 7 H +


    Triacylglycerol oxidation5
    Triacylglycerol Oxidation

    • The first step of the oxidation is catalyzed by Acyl-CoA dehydrogenase.

      • There are three types, differing in chain length specificity

        • LCAD - Long chain

        • MCAD - Medium chain

        • SCAD - Short chain

      • In New York State, all newborns are screened for MCAD deficiency

      • This disorder is covered in the “Baby Ian” case study on the MGB web site.


    Triacylglycerol oxidation6
    Triacylglycerol Oxidation

    • Oxidation of unsaturated fatty acids occurs by the beta oxidation pathway, but with two additional enzymes that isomerize (from cis to trans) and reduce the double bond(s).

    • Very long chain fatty acids chain fatty acids gre oxidized in peroxisomes to long chain amd medium chain acyl-CoA which enter the mitochondria via the carnitine shuttle. Adrenoleukodystrophy (ALD) is an X-lined disorder in which the entry of very long chain fatty acids into the peroxisome is blocked.



    Ketone bodies1
    Ketone Bodies

    • Ketone body synthesis - LIVER (mitochondria)

    OH O

    | ||

    CH3-C-CH2-C-S-CoA

    |

    CH2

    |

    COO -

    O

    ||

    CH3-C-S-CoA

    CoA

    O

    ||

    CH3-C-S-CoA

    O O

    || ||

    CH3-C-CH2-C-S-CoA

    Acetyl-CoA CoA

    2 Acetyl-CoA Acetoacetyl-CoA HMG-CoA

    mitochondrial!

    Acetyl-CoA

    NAD+ NADH+H+

    OH O

    | ||

    CH3-C-CH2-CO -

    O O

    || ||

    CH3-C-CH2-CO -

    -hydroxybutyrate Acetoacetate


    Ketone bodies2
    Ketone Bodies

    • Acetyl-CoA can be converted into ketone bodies:

      • Acetoacetate:

      • -hydroxybutyrate:

    • These are exported by the liver and used as fuel by other tissues

    • In a non-enzymatic side reaction, small amounts

      of acetone are produced from acetoacetate

    O O

    || ||

    CH3-C-CH2-CO -

    OH O

    | ||

    CH3-C-CH2-CO -

    O

    ||

    CH3-C-CH3


    Ketone body use
    Ketone Body Use

    NAD+ NADH+H+

    OH O

    | ||

    CH3-C-CH2-CO -

    O O

    || ||

    CH3-C-CH2-CO -

    -hydroxybutyrate Acetoacetate

    NOT

    present

    in liver

    Succinyl-CoA

    CoA transferase

    (thiphorase)

    O

    ||

    CH3-C-S-CoA

    Succinate

    2 Acetyl-CoA

    Acetoacetyl-CoA

    thiolase

    CoA


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