metabolism of dietary lipids
TRANSCRIPT
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Metabolism of dietary lipids
Biochemistry Department
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IntendedLearningOutcomes
By the end of this lecture , the student should becapable of:
1.Recognizing the different types of fatty acid
synthesis and oxidation.2.Finding the role of storage of fatty acid as TAG3. Identifying the fatty acid synthesis and degradation4.summarizing the synthesis and oxidation processes
of fatty acids.5.explaining the modes of regulation for TG & FA
metabolism
6.Describing some abnormalities in lipid metabolism
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Fatty Acids AndTriacylglycerol
Metabolism
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Remember from previously
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Breakdown Of Triacylglycerols To
Glycerol And Fatty Acids by HSL
FFA
ALBEnter tissue cells(?) to
be activated to Acyl-
CoA ready for
Oxidation to giveenergy
FFAsmoves from
adipocyte cell
membrane
Immediately in plasma
Remember: Regardless blood levels of plasma FFA cannot beused as fuel by erythrocytes(no mitochondria) or by the
brain (impermeable blood-brain barrier).
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Acyl CoA synthetase(Thiokinase) reactionoccurs in the on the mitochondrial
membrane in the cytoplasm( 2 ATP
utilized).
Activation of Fatty Acids
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Carnitine carries long-
chain activated fatty
acids into themitochondrial
Matrix.
Transport into Mitochondrial Matrix
Fatty acid is ready now
for oxidation lets start
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Sources of carnitine:1-diet ( meat products).2- Endogenous synthesized carnitine(lysine and methionine) by liver &kidneybutnot in skeletal or heart ms.
Although skeletal ms has 97% of allcarnitine in the body,they are dependent oncarnitine provided by blood from endogenoussynthesis or diet.
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Carnitine deficiencies results in a decreased abilityof tissues to use LCFA as a metabolic fuel.
CPT-Ideficiency( liver)
1ry carnitine deficiency:
=Congenital deficiencies in any of CPTsystem.
CPT-II deficiency(cardiac & skeletal ms)
Inability to use LCFAfor fuel impairs the
ability to synthesizeglucosein fast.Thisleads to: severehypoglycemia,coma,
& death
Cardiomyopathy
to muscle weaknesswith myoglobinemiafollowing prolongedExercise.
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Increased requirement for carnitine( pregnancy, severe infections, burns, or trauma.)
Hemodialysis patients(removes carnitine from the blood)
Treatment includes: avoidance of prolonged fasts,diet high in carbohydrate and low in LCFA, butsupplemented with medium-chain fatty acid and, in
cases of carnitine deficiency, carnitine.
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Fatty Acid Oxidation
Metabolism of ketone bodies
Fatty Acids And Triacylglycerol Metabolism
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Fatty Acid Oxidation
1-( )Beta-oxidation of FA FA TranActivation of sport of LCFA into mitochondria:(Carnitine shuttle-carnitine sources-carnitine deficiency) Entery of short and medium chain FA?
Steps of oxidation Energetics of oxidation Oxidation of unsaturated FA Oxidation of odd-number FA -oxidation in peroxisome for very long chain FA .
2-Aternative ways of oxidation()Alpha-oxidation of FA
()Omega-oxidation of FA
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Steps of-oxidation:4steps-For even saturated FAscycles= (n/2) 1= X times.
each = 1(acetyl CoA +NADH+FADH2). except the finalthiolytic cleavage produces 2acetyl CoA
[NB: Acetyl CoA is a positiveallosteric effector ofpyruvate carboxylasethuslinking FA oxidation and
gluconeogenesis.]
Oxidation
Hydration
Oxidation
Thiolase
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Energy yield from fattyacid oxidation: Theenergy yield is high.
For example, the oxidationof of palmitoyl CoA (16C)to CO2 and H2O produces8 acetyl CoA, 7 NADH, and
7 FADH2, from which 131ATP can be generated;however, activation of thefatty acid requires 2 ATP.So, net yield from
palmitate is 129 ATP.
16/2-1=7cycle= 7X17+12-2=
129 ATP
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Oxidation of odd number fatty acids :The -oxidation of a saturated odd FAproceeds the same as even until the finalthree carbons propionyl CoA is reached, it ismetabolized by a three-step pathway[Propionyl CoA is also produced during themetabolism of certain aa.
three-step pathway proceeds as follows
Special Cases
St
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Steps are:1-Synthesis of D-MMCoA frompropionyl CoA
2-Formation of L-methylmalonyl CoA
3- Synthesis ofsuccinyl CoA. L-MMCoA is rearranged,forming succinyl CoA,which enter (TCA)cycle. [Note: This isthe only example of aglucogenic precursorgenerated from fatty
acid oxidation.]
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Medium chain fatty acyl CoA dehydrogenase
deficiency(MCDA)
In mitochondria there are different typesof fatty acyl CoA dehydrogenases whichare specific for short, medium, long fatty
acids.An autosomal ressive disorder MCDAone of disorders ch ch by: defect inoxidation of middle chain fatty acids.Because, there is reliance on glucose sohypoglycemia on fasting should beavoided in these atients. MCDA has
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Oxidation of unsaturated fatty acids: Theoxidation of unsaturated FA provides lessenergy than saturated FA because unsaturated
FA are less reduced and, therefore, fewerreducing equivalents can be produced fromthese structures.Energy yield is less than that of the oxidationsaturated FA by 2 ATP less for each doublebond. (i.e. less production of reducingequivalent as the first step of beta oxidation
is skipped)
Special Cases
d h
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-Oxidation in the peroxisome: It is apreliminary step For shortening VLCFA, 22C, up to 8C. The Shortened FA istransferred to mitochondria for furtheroxidation. In contrast to mitochondrial -oxidation:
1- Initial dehydrogenation in peroxisomes is anFAD-containing acyl CoA oxidase. (HereFADH2 produced is oxidized by molecular
oxygen to H2O2). The H2O2 is reduced toH2O by catalase) .(no ATP by this step)Zellweger syndrome=Genetic defects in theprevious process leads to accumulation ofVLCFA + roduction of neurolo ical s m toms.
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-For Branched-chain FA, phytanic acid
(20C in brain): As its not a substrate foracyl CoA dehydrogenasedue to methylgroupon its third () carbon.-It is based on the hydroxylation of
alpha C then removal of C1 as CO2(Decarboxylation) at a time from thecarboxyl end of the FA.-It does not need CoA.
-It does not produce energy.
-Oxidation of fatty acids
-Refsum disease = A defect alpha-oxidationresults in accumulation of phytanic acid and
production of neurological symptoms.
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-Oxidation (in ER involving cytochromep450):Methyl terminus is oxidized tocarboxyl group and Beta oxidation proceedfrom both ends(dicarboxylic).Its a minor pathway, its up-regulation in MCADdeficiency
CH3CH2-CH2-(CH2)n-CH2-CH2-C00H
CH2--CH2-CH2-(CH2)n-CH2-CH2-C00H
0H
H00CCH2-CH2-(CH2)n-CH2-CH2-C00H
-oxidation
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Compare between :fatty acid synthesis and degradation
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Metabolism of ketone bodies
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Metabolism of ketone bodies
What are ketone bodies
What are their blood and urine levels ?
Ketogenesis
Ketolysis
ketosis
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Liver mitochondria can convert acetyl CoA
derived from FA oxidation into ketone bodies.The two functional KB are;
- (transported in theblood to the peripheral tissues),(a non-metabolized product goes out
with breath).
The functional water soluble KB can bereconverted to acetyl CoA, which can beoxidized by the TCA cycle.
Ketone Bodies: An Alternate Fuel For Cells
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Ketone Bodies Use of fatty acids in the citric acid cycle
requires carbohydrates for the the production ofoxaloacetate.
During starvation or diabetes, OAA is used tomake glucose. Fatty acids are then used to
make ketone bodies
Ketone Bodies as a Fuel SourceThe liver is the major source of ketone bodies.
They are transported in the blood to other
tissues (extra hepatic)
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Even though the citric acid cycle intermediate
oxaloacetate can be used to synthesize
glucose, AcetylCoA cannot be used to
synthesize oxaloacetate. The two carbons thatenter the citric acid cycle as AcetylCoA leave
as CO2.
Fatty Acids Cannot be Used to
Synthesize Glucose
when FA oxidation is high
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when FA oxidation is highin the Liver(Starvation-Diabetes-
Severe muscularexercise).Acetyl CoA amount
the capacity of
TCA to oxidize it;Why
Because there is notenough carbohydrates to
provide oxaloacetatefrom the
reaction So,KB are formed fromacet l CoA.
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Why are KB are important for peripheraltissues as a source of energy? Because theyare
1) Soluble in water do not need lipoproteins oralbumin as do the other lipids.
2) Produced in the liver when acetyl CoA
exceeds the oxidative capacity of the liver3) Used by extrahepatic tissues( skeletal,
cardiac, muscle and renal cortex). Even thebrain can use ketone bodies to help meet itsenergy needs if the blood levels risesufficiently to spare glucose.
4) Important during prolonged periods of
fasting, thus ketone bodies spare glucose
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A. Synthesis of ketone bodies by the liver:ketogenesis
, the liver is full with FA mobilized fromadipose tissue.
hepatic acetyl CoA from FA degradationwhich inhibits
and
The OAA thus produced is used by the liver forgluconeogenesis rather than for the TCA cycle.Therefore, acetyl CoA goes for ketone bodysynthesis.
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:
By reversal of the thiolase ofFA oxidation acetoacetyl CoA
is formed.
takes a
3rd acetyl CoA to produceHMG CoA (also a precursor
of cholesterol) .
is the
in
the synthesis of
, and is present only in
the liver
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Synthesis of the ketone
bodies: iscleaved to acetoacetate &
acetyl CoA.
Acetoacetate can bereduced to 3-
hydroxybutyrate withNADH
orspontaneously
decarboxylated intoacetone.
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equilibrium betweenand 3-hydroxybutyrate depends on
NAD+/NADH ratio.If the ratio is low as in FAoxidation, 3-OH-butyrate
is favored.
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B.
:
-Although the liver actively produces ketonebodies, it lacks
therefore, is unable to use asfuel.-In contrast, extrahepatic tissues, includingthe brain but excluding cells
(e.g. red blood cells),efficiently oxidize acetoacetate and 3-hydroxybutyrate in this manner.
Ketone body synthesis in the liver and use in peripheral tissues
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Ketone body synthesis in the liver and use in peripheral tissues.
3-OH-butyrate oxidized to acetoacetate bygiving NADH. Then,
Acetoacetate+succinyl CoA by special transferase(thiophorase) (reversible but giving 2 acetyl CoAs whichquickly removed to enters TCA for energy).
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leads to release offree fatty from adipose tissue directly to affectthe level of ketogenesis in the liver
C. Excessive production of ketone bodies in diabetes
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Mechanism of diabetic ketoacidosis seen in type 1 diabetes.
In severe ketosis,KB blood (ketonemia)
may reach 90 mg/dl (versusless than 3 mg/dl in normalindividuals).& urine (ketonuria) as
high as 5,000 mg/24 hr.
C. Excessive production of ketone bodies in diabetesmellitus leading to ketoacidosis HOW?
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(pKa=3.5) so theyof blood.
This acidity isdangerous because it
.
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:in the breath (acetone).
-Symptoms of as carboxyl group of a KB has a pKa of
about 4. Therefore, each ketone body loses a proton (H+) as itcirculates in the blood, which lowers the pH of the body.
, due to excretion of glucose and ketone bodiesin the urine.
Therefore, the increased number of H+, circulating in adecreased volume of plasma, can cause severe acidosis(ketoacidosis).
Other causes of ketosis other than Diabetes may be:
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