Metabolism of dietary lipids

7/29/2019 Metabolism of dietary lipids

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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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6

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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7

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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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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Metabolism of dietary lipids

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