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 CO 2 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 || CH 3 —C—S—CoA + HCO ATP Acetyl CoA O O || || - O—C—CH 2 —C—S—ACP + ADP + P i 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 || CH 3 —C—S—ACP Acetyl-ACP O O || || - O—C—CH 2 —C—S—ACP Malonyl-ACP

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

12 Dehydration and Reduction In reactions 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 (C 16 ) 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