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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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