1. Metabolism of dietary lipids Biochemistry Department

2. © I L O 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

3. Fatty Acids And Triacylglycerol Metabolism

4. Remember from previously

5. Breakdown Of Triacylglycerols To Glycerol And Fatty Acids by HSL FFA ALB Enter tissue cells(?) to be activated to Acyl- CoA ready for Oxidation to give energy FFAs moves from adipocyte cell membrane Immediately in plasma 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. 6 Acyl CoA synthetase(Thiokinase) reaction occurs in the on the mitochondrial membrane in the cytoplasm( 2 ATP utilized). Activation of Fatty Acids

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

8. Sources of carnitine: 1-diet ( meat products). 2- 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,they are dependent on carnitine provided by blood from endogenous synthesis or diet.

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

10. 2ry carnitine deficiency Liver disease Patients (decreased synthesis of carnitine). Increased requirement for carnitine ( pregnancy, severe infections, burns, or trauma.) Malnutrition patients (vegetarian) Hemodialysis patients (removes carnitine from the blood) Treatment includes: avoidance of prolonged fasts, diet high in carbohydrate and low in LCFA, but supplemented with medium-chain fatty acid and, in cases of carnitine deficiency, carnitine.

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

12. 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

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

14. Steps of β-oxidation:4steps -For even saturated FAs cycles= (n/2) – 1= X times. each = 1(acetyl CoA +NADH+ FADH2). 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.] Oxidation Hydration Oxidation Thiolase

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

17. 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, it is metabolized by a three-step pathway [Propionyl CoA is also produced during the metabolism of certain aa. three-step pathway proceeds as follows Special Cases

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

19. Medium chain fatty acyl CoA dehydrogenase deficiency(MCDA) In mitochondria there are different types of fatty acyl CoA dehydrogenases which are specific for short, medium, long fatty acids. An autosomal ressive disorder MCDA one of disorders ch ch by: defect in oxidation of middle chain fatty acids. Because, there is reliance on glucose so hypoglycemia on fasting should be avoided in these patients. MCDA has been originally reported to be a cause of some cases as sudden infant death syndrome (SIDS) or Reye syndrome.

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

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

22. -For Branched-chain FA, phytanic acid (20C in brain): As its not a substrate for acyl CoA dehydrogenase due to methyl group on its third (β) carbon. -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. -It does not produce energy. α-Oxidation of fatty acids -Refsum disease = A defect alpha-oxidation results in accumulation of phytanic acid and production of neurological symptoms.

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

24. Compare between : fatty acid synthesis and degradation

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

27. Ketone Bodies: An Alternate Fuel For Cells

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

29. 29 Even though the citric acid cycle intermediate oxaloacetate can be used to synthesize glucose, Acetyl–CoA cannot be used to synthesize oxaloacetate. The two carbons that enter the citric acid cycle as Acetyl–CoA leave as CO 2. Fatty Acids Cannot be Used to Synthesize Glucose

31. 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, cardiac, muscle and renal cortex). Even the brain can use ketone bodies to help meet its energy needs if the blood levels rise sufficiently to spare glucose. 4)Important during prolonged periods of fasting, thus ketone bodies spare glucose

37. Ketone body synthesis in the liver and use in peripheral tissues.

39. Mechanism of diabetic ketoacidosis seen in type 1 diabetes. C. Excessive production of ketone bodies in diabetes mellitus leading to ketoacidosis HOW ?