Ketone Bodies and Fatty Acid Synthesis

Question 1

Fatty Acid Degradation Summary

Answer 1

• Fatty acids are released from TAG in adipose
• Transported to tissues
• Activated from acyl CoA
• Transported to mitochondria

Question 2

What are Ketone bodies?

Answer 2

An alternative fuel source

Question 2

Where are Ketone bodies produced?

Answer 2

In mitochondria of the liver from acetyl CoA

Question 3

What do Ketone bodies produce?

Answer 3

Produce 2 functional ketone bodies
- acetoacetate and 3-hydroxybutyrate
- acetone excreted as non-metabolized by-product

Question 4

Where are ketone bodies exported to?

Answer 4

Exported from liver to heart, kidney, muscle and fasting brain

Question 5

Why are ketone bodies an important energy source for peripheral tissues?

Answer 5

1. Water soluble- no need for lipoproteins
2. Produced in liver when amount of acetly CoA exceeds oxidative capacity of liver
3. Used in proportion to their concentration in blood- can replace glucose- particularly important during long periods of fasting

Question 6

Use of ketone bodies

Answer 6

During fasting, production of ketone bodies increases
- Due to increased breakdown of FAs in liver leading to increased acetyl CoA production
- Ketone bodies are transported to the extrahepatic tissue in the blood
- taken up by tissues and metabolized to generate NADH and Acetyl CoA
- liver lacks thiolase so cannot use ketone bodies

Question 7

Ketogenic diet

Answer 7

• reliant on metabolizing fats
• promote ketone body formation by forcing body into starvation mode
• fats and ketone bodies become the main fuel source
• used to reduce seizures in children with drug resistant epilepsy (ketone bodies change gut microbiome)

Question 8

Diabetic ketosis

Answer 8

diabetes=lack of insulin=lack of glucose uptake in cells
- oxaloacetate consumed to make glucose in liver (TCA slows)
- lack of insulin=more fatty acid degradation
- increase in ketone body production in liver
- ketones are acidic and over production leads to acidosis (issue w/ proteins)

Question 8

Steps of Fatty Acid Synthesis

Answer 8

1. Transport of acetyl CoA from mitochondrial matrix to cytoplasm
2. Conversion of acetyl CoA to malonyl CoA
3. Synthesis of FA by FA synthase - a large enzyme with 7 catalytic functions

Question 9

Transport of Acetyl CoA to cytoplasm

Answer 9

• CoA cannot cross the inner mitochondrial membrane
• Acetyl-CoA converted to citrate to cross then back to Acetyl CoA in the cytoplasm at the cost of 1 ATP

Question 9

Citrate in the Cytoplasm

Answer 9

• Catalyzed by ATP-citrate lyase - stimulated by insulin
• All carbons in FA synthesis are contributed by Acetyl CoA
• For synthesis of palmitate transport and cleavage rxns must be repeated 8 times
• Citrate indicates energy rich state - inhibiting PFK (glycolysis)

Question 10

NADPH Requirements

Answer 10

• NADPH is required for reduction in FA synthesis (synthesis of palmitate requires 14 molecules of NADPH)
• 8 molecules of NADPH are produced in the transport of acetyl CoA to the cytoplasm rest from Pentose Phosphate Pathway

Question 10

What is Malonyl CoA?

Answer 10

Activated form of Acetyl CoA

Question 11

Formation of Malonyl CoA?

Answer 11

• Commited step in FA synthesis
• Formation catalyzed by acetyl coA carboxylase 1 (regulatory enzyme, req. ATP)
• Malonyl CoA is the C donor for all but two C atoms of palmitate

Question 12

Regulation of FA Synthesis

Answer 12

• Acetyl CoA carboxylase is a key regulator of FA metabolism - activated by insulin, inhibited by glucagon and epinephrine
• covalently inhibited by phosphorylation

Question 13

Acetyl CoA Carboxylase and Citrate

Answer 13

• Citrate allosterically induces polymerization of inactive dimers to form active filaments
• Palmitoyl CoA has the reverse affect

Question 14

Mitohcondrial Acetyl CoA Carboxylase

Answer 14

• An isoform of Acetyl CoA carboxylase is found in the mitochondria
• When energy levels are high, mitochondrial acetyl CoA carboxylase produces malonyl CoA which inhibits carnitine acyltransferase I
• This prevents the entry of FA into mitochondrion, inhibiting fatty acid degradation (high malonyl CoA, high FA synthesis, low FA degradation)

Question 15

Acyl Carrier Protein (ACP)

Answer 15

• ACP provides a foundation on which to build FA
• FA synthesis begins with formation of acetyl ACP and malonyl ACP

Question 16

What enzyme is required for fatty acid synthesis?

Answer 16

• FA synthase catalyzes all steps
• Steps are iteratively repeated, growing the chain by 2 C’s at a time

Question 17

What is the final product of FA synthesis?

Answer 17

Palmitate

Question 18

What does Thioesterase do?

Answer 18

Thioesterase catalyzes the release of C16-acyl group from ACP
- further elongation and desaturation require additional enzymes

Question 19

FA Synthase in Animals?

Answer 19

• multi-domain enzyme (9 diff domains, catalyzing each step)
• completetly symmetrical

Question 19

Further Elongation and Desaturation

Answer 19

• Longer-chain FAs are required by cells for various purposes

Question 20

Where does further elongation and desaturation occur?

Answer 20

ER

Question 21

What catalyzes formation of long chain FA using maloyl CoA

Answer 21

Membrane bound enzymes

Question 22

Where does unsaturation occur?

Answer 22

ER membrane

Question 23

What does unsaturation do?

Answer 23

• Produces precursors for important signalling molecules
• Lack the enzyme to introduce double bonds at C atoms beyond C-9 making linoleate and linolenate essential FA