1. Lipids Metabolism

2. Fatty acids TAG Complete oxidation of fatty acids to CO2 & H2O: 9 Kcal/gram of fat Fatty acids: are stored in adipose tissue, in the form of Triacylglycerol (TAG) = Glycerol + 3 Fatty Acids TAG: provide concentrated storage of metabolic energy Complete oxidation of fatty acids to CO2 & H2O: 9 Kcal/gram of fat Stored Fats

3. Fatty Acids Oxidation

4. Release of fatty acids from TAG in adipose tissue hormone-sensitive lipase (HSL) By hormone-sensitive lipase (HSL) ---- yields free fatty acids Glucagon EpinephrineACTIVE Glucagon & Epinephrine phosph. HSL ACTIVE fasting stateno (in fasting state, no glucose) cAMP Insulin INACTIVE Insulin dephosph. HSL INACTIVE fed state (fed state, glucose is available)

5. Fate of free fatty acids (released from TAG in adipose tissue) free Fatty acids (from adipose tissue TAG) Blood (bound with albumin) Cells of body FA Oxidation FA Oxidation (in mitochondria) Acetyl CoA Ketone Bodies Acetyl CoA Citric Acid Cycle (in liver) FFAs are oxidized in all tissues of the body EXCEPT: RBCs RBCs (no mitochondria) brain brain (BBB)

6.  -oxidation of fatty acids Fatty acids in cytosol are transported to mitochondria  -oxidation of fatty acids occurs In the mitochondria Two carbon fragments are successively removed from carboxyl end of the fatty acid producing acetyl CoA, NADH & FADH2 Fatty Acid Fatty Acid (n carbons) Fatty acid Acetl CoA Fatty acid (n -2 carbons) + Acetl CoA + NADH + FADH2

7. Transport of Fatty acids to mitochondria 1- Long-chain fatty acids FAs longer than 12 carbons carinitine carnitine shuttle Long-chain fatty acids are transported to the mitochondria by carinitine using carnitine shuttle Enzymes of the carinitine shuttle: Enzymes of the carinitine shuttle: Carnitine Acyltransferase-I (CAT-I) Carnitine Acyltransferase-II (CAT-II)

8. Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont. Carinitine Shuttle & Enzymes

9. Sources of carinitine: Sources of carinitine: Diet - Diet : particularly in meat products Synthesized: - Synthesized: From amino acids lysine & methionine in liver & kidney BUT not: in sk.ms & heart Inhibitor of carinitine shuttle Inhibitor of carinitine shuttle fatty acid synthesis in the cytosol - occurrence of fatty acid synthesis in the cytosol (indicated by malonyl CoA) acetyl CoA / CoA ratio - increased acetyl CoA / CoA ratio Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

10. Carnitine deficiencies Carnitine deficiencies Lead to decreased ability of tissues to use long-chain FAs as sources of fuel as they are not transported to the mitochondria Secondary causes: - liver diseases: decreased synthesis of carnitine - Malnutrition or strictly vegetarians: diminshed carnitine in food - Increased demand for carnitine e.g. In fever, pregnancy, etc - Hemodialysis due to removal of carnitine from blood Primary carinitine deficiencies: caused by congenital deficiencies of : - one of enzymes of the carnitine shuttle (next slide) - one of the components of renal tubular reabsorption o f carnitine - one of the components of carnitine uptake of carnitine by cells Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

11. CPT-I deficiency: CPT-I deficiency: - Affects the liver - liver is unable to utilize long-chain fatty acids as a fuel cannot - So, liver cannot perform gluconeogenesis (synthesis of glucose during fasting) coma Hypoglycemia occurs, might lead to coma CPT-II deficiency: CPT-II deficiency: - Affects primarily the skeletal & cardiac muscles - Symptoms : Cardiomyopathy Muscle weakness Treatment of carinitine deficiencies Treatment of carinitine deficiencies - Avoiding prolonged fasting - Diet should be rich in carbohydrates, low in long-chain fatty acids & supplemented with medium chain fatty acids Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

12. 2- Short- & medium- chain fatty acids FAs shorter than 12 carbons FAs shorter than 12 carbons Can cross the inner mitochondrial membrane without aid of carinitine Transport of Fatty acids to Mitochondria Transport of Fatty acids to Mitochondria cont.

13. Reactions of  -oxidation

14. Medium Chain Fatty acyl acyl CoA Dehydrogenase Deficiency (MCAD) Autosomal recessive disorder Autosomal recessive disorder One of the most common inborn errors of metabolism The most common inborn error of fatty acid oxidation (1:40000 worldwide births) Cause decrease of fatty acid oxidation Severe hypoglycemia Severe hypoglycemia occurs (as tissues do not get use fatty acids as a source of energy & must rely on glucose) Infants are particularly affected by MCAD deficiency as they rely on milk which contains primarily MCAD Treatment: carbohydrate rich diet Treatment: carbohydrate rich diet

15. Energy Yield from Fatty Acid Oxidation Palmitatic acid as an example: Complete  -oxidation of palmotyl CoA (16 carbons) produces : - 8 acetyl CoA ----- Kreb Cycle TCA cycle ------ 8 X 12 = 96 ATP - 7 NADH ----------- ETC ----------------------------- 7 X 3 = 21 ATP - 7 FADH2---------- ETC ----------------------------- 7 X 2 = 14 ATP ------------- All yield ---------------------------------------------------------131 ATPs Activation of fatty acid requires 2 ATP Net energy gained: 129 ATPs from one molecule of palmitate

16. Oxidation of Branched-Chain Fatty Acids Branched-chain fatty acids as phytanic acid is catabolised by  -oxidation by  -hydroxylase Refsum disease Deficiency of a-hydroxylase deficiency results in accumulation of phytanic acid in blood & tissues with mainly neurologic symptoms (Refsum disease) It is treated by diet restriction to reduce disease progression

17. Ketone Bodies Metabolism

18. Ketone Bodies Liver mitochondria can convert acetyl CoA derived from the oxidation of fatty acids to ketone bodies which are: 1- Acetoacetate 1- Acetoacetate 2- 3-hydroxybutyrate (or  -hydroxybutyrate) 2- 3-hydroxybutyrate (or  -hydroxybutyrate) 3- Acetone (nonmetabolized side product) 3- Acetone (nonmetabolized side product) Acetoacetate & 3-hydroxybutyrate synthesized in the liver are transported via blood to peripheral tissues In peripheral tissues, they can be converted to acetyl CoA Acetyl CoA is oxidized by citric acid cycle to yield energy (ATPs)

19. Ketone bodies are important sources of energy for peripheral tissues: 1- They are soluble in aqueous solution, so do not need to be incorporated into lipoproteins or carried by albumin as do other lipids 2- They are synthesized in the liver when amount of acetyl CoA exceeds oxidative capacity of liver 3- They are important sources of energy during prolonged periods of fasting especially for the brain as: - Can pass BBB (while FAs cannot) - Glucose in blood available in fasting is not sufficient Ketone Bodies Ketone Bodies cont.

20. Synthesis of ketone bodies in the liver (Ketogenesis) fatty acids During a fast, liver is flooded by fatty acids mobilized from adipose tissue acetyl CoA FAs are oxidised to acetyl CoA in large amounts Acetyl CoA does not find enough oxalacetate to be incorporated in TCA cycle ketone bodies So, excess acetyl CoA is shifted to ketone bodies formation

21. Reactions of ketone bodies synthesis

22. Use of Ketone bodies by peripheral tissues (Ketolysis) cannot Liver cannot use ketone bodies as a fuel peripheral tissues Use of ketone bodies occurs in peripheral tissues 3-hydroxybutyrate (KB) Acetoacetate (KB) Acetoacetyl CoA 2 acetyl CoA 2 acetyl CoA

23. Ketogenesis & Ketolysis

24. Excessive Production of Ketone Bodies in Diabetes Mellitus

25. Ketonemia (increased KB in blood) occurs when occurs when rate of production of ketone bodies (KETOGENESIS) is greater than rate of their use (KETOLYSIS) Excessive Production of Ketone Bodies in Diabetes Mellitus

26. in uncontrolled type 1 DM (Insulin-dependent DM) Increased lipolysis in adipose tissues with increased FFAs in blood High oxidation of fatty acids in liver Excessive amounts of acetyl CoA + Depletion of NAD+ pool (required by citric acid cycle) Acetyl CoA is shifted to ketone bodies synthesis in liver DIABETIC KETOACIDOSIS, (DKA) (with Ketonemia & ketonuria) Excessive Production of Ketone Bodies in Diabetes Mellitus

27. Manifestations of Diabetic Ketoacidosis ketonemia ketonemia: KB in blood more than 3 mg/dl, may reach 90 mg/dl Ketonuria Ketonuria: KB in urine may reach 5000 mg/24 hours Fruity odour on the breath Fruity odour on the breath :due to increased acetone production Acidosis & acidemia Acidosis & acidemia Dehydration Dehydration : due to increased urine volume due to excess excretion of KB & glucose Excessive Production of Ketone Bodies in Diabetes Mellitus