1. THE KETONE BODIES: FROM PROVIDERS OF ENERGY FOR LIFE TO FATAL KILLERS By Prof Morsi Arab University of Alexandria, Egypt

2. Storage The Fed State

3. Body Energy in {The Fed State} 1. Provision of Energy : by continuous supply from ingested glucose and fat. 2. Storing of Energy : In the liver: (Glycogen ) up to 1000 Kcal In Fat Depots (TG) up to 100000 Kcal 3 Tissue utilization of fuel for Energy: All Tissues can use glucose or FA. Except the Brain, only glucose.

4. In The { Fasting } and { Starvation } States I. In An Over night Fast 1. Glycogen stores are depleted …….(shortage of glucose) 2. Fat has to be utilized for energy : (TG)  FA + Glycerol (oxidation for energy) (is used for neoglucogenesis  in the liver ) Acetyl CoA  Ketone Bodies (KB) ………………… up to 0.1 - 0.4 mM II. In Prolonged Fasting ( Starvation ) … up to 7-10 mM

5. Adipose Tissue Blood Insulin Lipolysis FFA Delivery KB X FFA Muscles Brain Utilization Liver Ketogenesis Glucagon Insulin

6. Ketogenesis What is it and What For ? Ketogenesis is the conversion of long chain FA to the Four carbon acetoacetate and 3 hydroxy butyrate ( Ketone Bodies: KB). The primary utility of ketogenesis is to provide a universally accepted * fuel for energy production… ( an adaptive response in starvation) *The Brain oxidizes KB but not Fat. *Other Tissues oxidize KB and Fat.

7. Ketosis or Keto-Acidosis A large accumulation of KB is dangerous, because it leads to profound metabolic acidosis. The physiologic Ketogenesis of fasting and the adaptive ketosis in starvation never progress to life threatening acidosis

8. The Chemical Sequence from FA to KB (through Acetyl Co A) 2 Acetyl Co A  2 Acetoacetyl CoA+CoA Aceto acetyl Co A +Acetyl Co A  Hydoxymethyl Glutaryl Co A 3. Hyrdoxymethyl Glutaryl Co A  Acetoacetate + Acetyl Co A 4. Acetoacetate + NADH = H2  3-Hydroxy Butyrate

9. The “Mitochondria” and the “Carnitine CoA Shuttle” The mitochondria play a major role in ketogenesis. Medium chain FA easily enter the mitochondria, but Long chain FA require a shuttle to get inside (The Carnitine CoA Shuttle)

10. Carnitine Shuttle

11. The Carnitine CoA Shuttle Reaction LCFA (outside MC)-----------------  Carnitine (Carnitine Palmitoyl Transferase I- CPT I) Carnitine -----------------  LCFA (inside MC ) (Carnitine Palmitoyl Transferase II – CPT II) ……………………………………………….. Therefore, the CPT I enzyme is a key control in FA oxidation and in Ketogenesis

12. Carnitine FA Malonyl CoA KB X Acetyl Co A Glucagon CPT1 CPT II X Co A

13. The role of “Malonyl Co A” in Ketogenesis Malonyl Co A is derived from Acetyl Co A A high level of Malonyl Co A in the hepatocyte inhibits the activity of CPT I and so it damps down ketogenesis. Insulin increases the production of Malonyl Co A from Acetyl Co A

14. The Role of Insulin in Ketogenesis Lack of insulin has been long known to be related to development of ketosis. The presence of Insulin blocks Lipolysis, the source of FFA delivery to the liver, the substrate needed for ketogenesis. Insulin increases poduction of Malonyl Co A (so, inhibits CPT I …damps ketogenesis, inspite of any increased substrate FFA delivery)

15. Glucagon and Ketogenesis Diabetes is not only a disease of Insulin deficiency but also excess Glucagon. Glucagon has ketogenic activity. It plays this role in regulation of ketogenesis independent from insulin.. ( It activates FA oxidation at the expense of TG synthesis The Glucagon / Insulin ratio is more important than the absolute value of either, in determining the metabolic events in the hepatocyte

16. The main factors which control Ketogenesis in the liver 1.Availability of the substrate (Long Chain Fatty Acids) : from increased production by lipolysis with increased delivery of FA to the liver. 2.The level of Malonyl Co A in the liver, with its influence to inhibit the Carnitine Palmitoyl Transferase I (CPT I) 3.The Glucagon / Insulin Ratio : a high ratio increases lipolysis and activation of oxidative ketogenesis, a low ratio counteracts ketogenisis

17. Ketogenesis under Patho- physiolocal states

18. Ketone Bodies in Obesity 1.In obesity, FFA and KB levels are elevated (independent on normal or impaired glucose tolerance) 2.KB Clearance is also diminished. 3.But, following an oral glucose load FFA and KB levels are lowered.

19. Ketone Bodies in Type 2 Diabetes 1 FFA and KB are usually elevated (circulating KB may increase 3 folds in non obese diabetics even if FFA are normal.) N.B. Why KB level is increased in type 2 diabetes inspite of increased insulin (which should counteract ketogenesis ) ? - because of an also increased Glucagon, (with finally a lower Insulin / Glucagon ratio)

20. Ketone Bodies in Type 1 Diabetes 1.Insulin is deficient 2. FFA and KB are increased, ketogenesis is activated to provide energy source substitute. 3. FFA uptake across the splancnic area is increased. Delivery of FFA substrate to the liver is not blocked (absence of the blocking effect of insulin ) 3. KB Clearance is diminished. 4. An unrestricted KB accumulation leads to metabolic acidosis (Diabetic Keto-acidosis )

21. Ketone Bodies in Hyperthyroidism 1. Increased lipolysis ( more FFA) = augmented substrate delivery 2. Increased lipid oxidation. All levels of FFA, Glycerol and KB are elevated.

22. Alexandrie – Palais du Montazah Thank You