Transcript Triacylglycerol Metabolism Gone Bad: A major cause of disease

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
• As it is synthesized, VLDL contains:
•
•
•
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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 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
Lipases
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 Oxidation
• Glycerol can be converted to glucose
– Glycerol kinase is present in liver but not normally present in
adipose
H2C-OH
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HOCH O
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H2C-O-P-O ||
O-
H2C-OH
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HOCH
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H2C-OH
Glycerol
Glycerol kinase
ATP
H2C-OH
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O=C O
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H2C-O-P-O ||
Glycerol-3Ophosphate
dehydrogenase
Glycerol-3-Phosphate
DHAP
NAD+
NADH + H +
ADP + Pi
Triacylglycerol Oxidation
• Fatty acids must be activated to Acyl-CoA
Fatty acid + CoA + ATP
Acyl-CoA + AMP + PPi
Acyl-CoA synthetase
PPi + H2O
2 Pi
Pyrophosphatase
Triacylglycerol Oxidation
Regulation
• 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 Oxidation
• Carnitine Shuttle
Inhibited by
Malonyl-CoA
Acyl-CoA + Carnitine
Acyl-Carnitine + CoA
CAT-I
CAT-II
CAT-II
Acyl-CoA + Carnitine
Acyl-Carnitine + CoA
Mitochondrion
Inner membrane
CAT - Carnitine Acyl-CoA Transferase
Outer membrane
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 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 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 Xlined disorder in which the entry of very long chain
fatty acids into the peroxisome is blocked.
Ketone Bodies
Ketone Bodies
• Ketone body synthesis - LIVER (mitochondria)
O
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CH3-C-S-CoA
O
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CH3-C-S-CoA
CoA
O
O Acetyl-CoA
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CH3-C-CH2-C-S-CoA
2 Acetyl-CoA
Acetoacetyl-CoA
OH
O
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CH3-C-CH2-C-S-CoA
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CoA CH
2
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COO -
HMG-CoA
mitochondrial!
Acetyl-CoA
OH
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O
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NAD+
CH3-C-CH2-CO -
-hydroxybutyrate
NADH+H+
O
O
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CH3-C-CH2-CO -
Acetoacetate
Ketone Bodies
• Acetyl-CoA can be converted into ketone
bodies:
O
O
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– Acetoacetate:
CH3-C-CH2-CO
– -hydroxybutyrate:
OH
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O
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CH3-C-CH2-CO -
• 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
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CH3-C-CH3
Ketone Body Use
OH
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O
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NAD+
NADH+H+
O
O
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CH3-C-CH2-CO -
CH3-C-CH2-CO -
-hydroxybutyrate
NOT
present
in liver
O
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CH3-C-S-CoA
Acetoacetate
CoA transferase
(thiphorase)
2 Acetyl-CoA
Succinyl-CoA
Succinate
Acetoacetyl-CoA
thiolase
CoA