Metabolic Pathways for Lipids.

1. Metabolic Pathways for Lipids. Ketogenesis and Ketone Bodies.Fatty Acid Synthesis.

2. Ketogenesis and Ketone Bodies In ketogenesis: • Body fat breaks down to meet energy needs. • Keto compounds called ketone bodies form.

3. Ketogenesis and Ketone Bodies In ketogenesis: • Large amounts of acetyl CoA accumulate. • Two acetyl CoA molecules combine to form acetoacetyl CoA. • Acetoacetyl CoA hydrolyzes to acetoacetate, a ketone body. • Acetoacetate reduces to -hydroxybutyrate or loses CO2 to form acetone, both ketone bodies.

4. Reactions of Ketogenesis Ketone bodies

5. Ketosis Ketosis occurs: • In diabetes, diets high in fat, and starvation. • As ketone bodies accumulate. • When acidic ketone bodies lowers blood pH below 7.4 (acidosis).

6. Ketone Bodies and Diabetes • The blood glucose is elevated within 30 min following a meal containing carbohydrates • The elevated level of glucose stimulates the secretion of insulin, which increases the flow of glucose into muscle and adipose tissue for synthesis of glycogen (+ stimulates glycolysis) • As blood glucose levels drop, the secretion of glucagon increases, which stimulates the breakdown of glycogen in the liver to yield glucose

7. Ketone Bodies and Diabetes In diabetes: • Insulin does not function properly. • Glucose levels in muscle, liver, and adipose tissue are insufficient for energy needs. • As a result, liver cells synthesize glucose from non-carbohydrate sources (gluconeogenesis) and fats are broken down to acetyl CoA. • The level of acetyl CoA is elevated. • Excess acetyl CoA undergoes ketogenesis. • Ketogenesis produces ketone bodies. • Ketone bodies accumulate in the blood.

8. Lipogenesis: Fatty Acid Synthesis Lipogenesis: • Is the synthesis of fatty acids from acetyl CoA. • Occurs in the cytosol. • Uses reduced coenzyme NADPH (NADH with a phosphate group). • Requires an acyl carrier protein (ACP).

9. Malonyl CoA In lipogenesis, acetyl CoA combines with bicarbonate to form malonyl CoA. ATP hydrolysis provides energy. O || CH3—C—S—CoA + HCO3- + ATP Acetyl CoA O O || || -O—C—CH2—C—S—ACP + ADP + Pi Malonyl CoA

10. Formation of Acetyl and Malonyl ACP Acetyl CoA and malonyl CoA combine with acyl carrier protein (ACP) to form acetyl-ACP and malonyl-ACP: O || CH3—C—S—ACP Acetyl-ACP O O || || -O—C—CH2—C—S—ACP Malonyl-ACP

11. Condensation and Reduction Inreactions 1 and 2 of fatty acid synthesis: • Condensation by a synthase combines acetyl-ACP with malonyl-ACP to form acetoacetyl-ACP (4C) and CO2 (reaction 1). • Reduction converts a ketone to an alcohol using NADPH (reaction 2).

12. Dehydration and Reduction Inreactions 3 and 4 of fatty acid synthesis: • Dehydration forms a trans double bond (reaction 3). • Reduction converts the double bond to a single bond using NADPH (Reaction 4).

13. Lipogenesis Cycle Repeats Fatty acid synthesis continues: • Malonyl-ACP combines with the four-carbon butyryl-ACP to form a six-carbon-ACP. • The carbon chain lengthens by two carbons each cycle.

14. Lipogenesis Cycle Completed • Fatty acid synthesis is completed when palmitoyl ACP reacts with water to give palmitate (C16)and free ACP.

15. Summary of Lipogenesis

16. Fatty Acid Formation • Shorter fatty acids undergo fewer cycles. • Longer fatty acids are produced from palmitate using special enzymes. • Unsaturated cis bonds are incorporated into a 10-carbon fatty acid that is elongated further. • When blood glucose is high, insulin stimulates glycolysis and pyruvate oxidation to obtain acetyl CoA to form fatty acids.

17. Comparing  Oxidation and Fatty Acid Synthesis