Biochemistry Department

Metabolism of dietary lipids

Intended Learning Outcomes
By the end of this lecture , the student should be capable of: 1. Recognizing the different types of fatty acid synthesis and oxidation. 2. Finding the role of storage of fatty acid as TAG 3. Identifying the fatty acid synthesis and degradation 4. 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 And Triacylglycerol Metabolism

Remember from previously

.Breakdown Of Triacylglycerols To Glycerol And Fatty Acids by HSL FFAs moves from adipocyte cell membrane ALB FFA Immediately in plasma Enter tissue cells(?) to be activated to AcylCoA ready for Oxidation to give energy Remember: Regardless blood levels of plasma FFA cannot be used as fuel by erythrocytes(no mitochondria) or by the brain (impermeable blood-brain barrier).

6 .Activation of Fatty Acids Acyl CoA synthetase(Thiokinase) reaction occurs in the on the mitochondrial membrane in the cytoplasm( 2 ATP utilized).

Fatty acid is ready now for oxidation lets start 7 .Transport into Mitochondrial Matrix Carnitine carries longchain activated fatty acids into the mitochondrial Matrix.

they are dependent on carnitine provided by blood from endogenous synthesis or diet.Sources of carnitine: 1-diet ( meat products).Endogenous synthesized carnitine (lysine and methionine) by liver &kidney but not in skeletal or heart ms. Although skeletal ms has 97% of all carnitine in the body. 2. .

Carnitine deficiencies results in a decreased ability of tissues to use LCFA as a metabolic fuel. & death Cardiomyopathy to muscle weakness with myoglobinemia following prolonged Exercise. .coma.This leads to: severe hypoglycemia. CPT-I deficiency ( liver) CPT-II deficiency (cardiac & skeletal ms) Inability to use LCFA for fuel impairs the ability to synthesize glucosein fast. 1ry carnitine deficiency: =Congenital deficiencies in any of CPT system.

or trauma. burns. but supplemented with medium-chain fatty acid and. severe infections.Hemodialysis patients (removes carnitine from the blood) Increased requirement for carnitine ( pregnancy. in cases of carnitine deficiency. .) Treatment includes: avoidance of prolonged fasts. carnitine. diet high in carbohydrate and low in LCFA.

Fatty Acids And Triacylglycerol Metabolism • Fatty Acid Oxidation • Metabolism of ketone bodies .

 2-Aternative ways of oxidation ()Alpha-oxidation of FA ()Omega-oxidation of FA .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 .

.Even FA produces only acetyl CoA . that cannot give glucose but Propionyl CoA is glucogenic. -Even FA(-2C) acetyl CoA+ NADH+ FADH2 -Odd FA ->1 propionyl CoA(3C) & (n) acetyl CoA -Each cycle produces 5ATPs.In mitochondria matrix. .) .β-Oxidation of fatty acids (major catabolic path.

except the final thiolytic cleavage produces 2 acetyl CoA [NB: Acetyl CoA is a positive allosteric effector of pyruvate carboxylase thus linking FA oxidation and gluconeogenesis. each = 1(acetyl CoA +NADH+ FADH2).] Oxidation Hydration Oxidation Thiolase .Steps of β-oxidation:4steps -For even saturated FAs cycles= (n/2) – 1= X times.

from which 131 ATP can be generated. and 7 FADH2. however. So. For example. the oxidation of of palmitoyl CoA (16C) to CO2 and H2O produces 8 acetyl CoA. net yield from palmitate is 129 ATP. activation of the fatty acid requires 2 ATP. 7 NADH.Energy yield from fatty acid oxidation: The energy yield is high. 16/2-1=7cycle= 7X17+12-2= 129 ATP .

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Special Cases Oxidation of odd number fatty acids : The β-oxidation of a saturated odd FA proceeds the same as even until the final three carbons propionyl CoA is reached. three-step pathway proceeds as follows . it is metabolized by a three-step pathway [Propionyl CoA is also produced during the metabolism of certain aa.

Steps are: 1-Synthesis of DMMCoA from propionyl CoA 2-Formation of Lmethylmalonyl CoA 3. forming succinyl CoA. L-MM CoA is rearranged.Synthesis of succinyl CoA.] . which enter (TCA) cycle. [Note: This is the only example of a glucogenic precursor generated from fatty acid oxidation.

medium. An autosomal ressive disorder MCDA one of disorders ch ch by: defect in oxidation of middle chain fatty acids. there is reliance on glucose so hypoglycemia on fasting should be avoided in these patients. long fatty acids. Because.Medium chain fatty acyl CoA dehydrogenase deficiency(MCDA) In mitochondria there are different types of fatty acyl CoA dehydrogenases which are specific for short. MCDA has .

less production of reducing equivalent as the first step of beta oxidation is skipped) . fewer reducing equivalents can be produced from these structures.Special Cases Oxidation of unsaturated fatty acids: The oxidation of unsaturated FA provides less energy than saturated FA because unsaturated FA are less reduced and.e. (i. therefore. Energy yield is less than that of the oxidation saturated FA by 2 ATP less for each double bond.

.Initial dehydrogenation in peroxisomes is an FAD-containing acyl CoA oxidase.  22C. The H2O2 is reduced to H2O by catalase) . (Here FADH2 produced is oxidized by molecular oxygen to H2O2). In contrast to mitochondrial βoxidation: 1. up to 8C.(no ATP by this step) Zellweger syndrome=Genetic defects in the previous process leads to accumulation of VLCFA + production of neurological symptoms. The Shortened FA is transferred to mitochondria for further oxidation.β-Oxidation in the peroxisome: It is a preliminary step For shortening VLCFA.

-Refsum disease = A defect alpha-oxidation results in accumulation of phytanic acid and production of neurological symptoms. -It does not produce energy. phytanic acid (20C in brain): As its not a substrate for acyl CoA dehydrogenase due to methyl group on its third (β) carbon.α-Oxidation of fatty acids -For Branched-chain FA. . -It is based on the hydroxylation of alpha C then removal of C1 as CO2 (Decarboxylation) at a time from the carboxyl end of the FA. -It does not need CoA.

Its a minor pathway.ω-Oxidation (in ER involving cytochrome p450):Methyl terminus is oxidized to carboxyl group and Beta oxidation proceed from both ends(dicarboxylic). its up-regulation in MCAD deficiency β α CH3 –CH2-CH2-(CH2)n-CH2-CH2-C00H CH2--CH2-CH2-(CH2)n-CH2-CH2-C00H 0H α β β α H00C—CH2-CH2-(CH2)n-CH2-CH2-C00H Β-oxidation .

Compare between : fatty acid synthesis and degradation .

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Metabolism of ketone bodies      What are ketone bodies What are their blood and urine levels ? Ketogenesis Ketolysis ketosis .

(transported in the blood to the peripheral tissues). The two functional KB are. . The functional water soluble KB can be reconverted to acetyl CoA. which can be oxidized by the TCA cycle. (a non-metabolized product goes out with breath).Ketone Bodies: An Alternate Fuel For Cells Liver mitochondria can convert acetyl CoA derived from FA oxidation into ketone bodies.

Fatty acids are then used to make ketone bodies Ketone Bodies as a Fuel Source The liver is the major source of ketone bodies. • During starvation or diabetes. They are transported in the blood to other tissues (extra hepatic) .Ketone Bodies • Use of fatty acids in the citric acid cycle requires carbohydrates for the the production of oxaloacetate. OAA is used to make glucose.

Acetyl–CoA cannot be used to synthesize oxaloacetate. 29 .Fatty Acids Cannot be Used to Synthesize Glucose Even though the citric acid cycle intermediate oxaloacetate can be used to synthesize glucose. The two carbons that enter the citric acid cycle as Acetyl–CoA leave as CO2.

when FA oxidation is high in the Liver (Starvation-DiabetesSevere muscular exercise). KB are formed from acetyl CoA. Acetyl CoA amount the capacity of TCA to oxidize it. Why Because there is not enough carbohydrates to provide oxaloacetate from the reaction So. .

4) Important during prolonged periods of fasting. Even the brain can use ketone bodies to help meet its energy needs if the blood levels rise sufficiently to spare glucose. thus ketone bodies spare glucose . cardiac.Why are KB are important for peripheral tissues as a source of energy? Because they are 1) Soluble in water do not need lipoproteins or albumin as do the other lipids. 2) Produced in the liver when acetyl CoA exceeds the oxidative capacity of the liver 3) Used by extrahepatic tissues( skeletal. muscle and renal cortex).

Therefore. . the liver is full with FA mobilized from adipose tissue.  hepatic acetyl CoA from FA degradation which inhibits and The OAA thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle.A. Synthesis of ketone bodies by the liver: ketogenesis . acetyl CoA goes for ketone body synthesis.

is the in the synthesis of . takes a 3rd acetyl CoA to produce HMG CoA (also a precursor of cholesterol) .: By reversal of the thiolase of FA oxidation acetoacetyl CoA is formed. and is present only in the liver .

Synthesis of the ketone bodies: is cleaved to acetoacetate & acetyl CoA. Acetoacetate can be reduced to 3hydroxybutyrate with NADH or spontaneously decarboxylated into acetone. .

equilibrium between and 3hydroxybutyrate depends on NAD+/NADH ratio. If the ratio is low as in FA oxidation. 3-OH-butyrate is favored. .

extrahepatic tissues.B. . it lacks therefore. -In contrast. red blood cells). : -Although the liver actively produces ketone bodies. is unable to use as fuel.g. including the brain but excluding cells (e. efficiently oxidize acetoacetate and 3hydroxybutyrate in this manner.

Then. . 3-OH-butyrate oxidized to acetoacetate by giving NADH.Ketone body synthesis in the liver and use in peripheral tissues. Acetoacetate+succinyl CoA by special transferase (thiophorase) (reversible but giving 2 acetyl CoAs which quickly removed to enters TCA for energy).

leads to release of free fatty from adipose tissue directly to affect the level of ketogenesis in the liver .

KB blood (ketonemia) may reach 90 mg/dl (versus less than 3 mg/dl in normal individuals).C. Excessive production of ketone bodies in diabetes mellitus leading to ketoacidosis HOW? Mechanism of diabetic ketoacidosis seen in type 1 diabetes. In severe ketosis. & urine (ketonuria) as high as 5. .000 mg/24 hr.

This acidity is dangerous because it .(pKa=3. .5) so they of blood.

. can cause severe acidosis (ketoacidosis). -Symptoms of as carboxyl group of a KB has a pKa of about 4. which lowers the pH of the body. due to excretion of glucose and ketone bodies in the urine. : Other causes of ketosis other than Diabetes may be: . circulating in a decreased volume of plasma. the increased number of H+.in the breath (acetone). each ketone body loses a proton (H+) as it circulates in the blood. Therefore. Therefore.

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