Lipid Metabolism

Question 1

Lipogenesis

Answer 1

• Storing energy in fat

Question 2

Citrate / Pyruvate Shuttle and Fatty Acid Synthesis

Answer 2

• De novo fatty acid synthesis uses acetyl-CoA to build up fatty acids
• But Fatty acid synthesis happens in the cytoplasm, while acetyl-CoA is in the mitochondria
  
  • Acetyl-CoA is shuttled out of the mitochondria through citrate

Question 3

Fatty Acid Synthesis

Answer 3

• Addign 2 carbons at a time onto a growing fatty acid chain
• A series of steps starting with acetyl-CoA that adds 2C units to a growing fatty acid chain
• Happens in the Liver and Adipose
• Uses NADPH instead of NADH
• Carefully regulated, primarily by acetyl-CoA carboxylase
• Deactivated by Phosphorylation by AMP-Activated Kinase or glucagon signaling (low-energy situation) or epinephrine signaling (high energy mobility situation)
• Activaed by high citrate and by dephosphorylation by insulin signaling (high energy situation)

Question 4

Triglyceride Synthesis

Answer 4

• Fatty acids are further processed into triglycerides (glycerol backbone) for storage
  
  • Glycerol comes from glucolysis dihydroxyacetone phsphate which is reduced to glycerol-3-phosphate
• 3 fatty acids are added in stepwise fashion to position 1, then 2, then 3
  
  • If the process is stopped after adding fatty acids to only positions 1 and 2, diacylglycerol phosphate is produced and can be used for membrane lipid synthesis
• Tryiglyceride synthesis happens in Liver and Aidpose
  
  • In adipose it is stored
  • In Liver it is transported to the rest of te body by very low density lipoprotein

Question 5

Lipolysis

Answer 5

• Using energy from fat
• Step 0:
  
  • a: Hormone sensitive Lipase/Monoacylglycerol Lipase
  • b: Fatty Acyl CoA Synthetase
• Step 1: Acyle-CoA Dehydrogenase
• Step 2: Enoyl-CoA Hydratase
• Step 3: 3-hydroxyacyl-CoA Dehydrogenase
• Step 4: Thiolase

Question 6

Step 0a: Hormone Sensitive Lipase/Monoacylglycerol Lipase

and

Step 0b: Fatty Acyl CoA Synthetase

Answer 6

• Step 0a: Hormone Sensitive Lipase/Monoacylglycerol Lipase
  
  • Main control point of Lipogenesis
  • Rgulated by INsulin/Epinephrine
• Step 0b: Fatty Acyl CoA Synthetase
  
  • Step 0 (activation) reactions happen in the cytosol, but all further steps happen in the mitochondria
  • Fatty acyl CoA cannot cross the mitochondrial membrane
  • How can we get FA-C into mitochondria?
    
    • Carnitine Shuttle

Question 7

Carnitine Shuttle

Answer 7

1. Carnitine binds with Acyl CoA by CPT1
2. Transports across the membrane by translocase
3. Carnitine seperates from Acyl CoA by CPT1

Question 8

Step 1: Acyl-CoA Dehydrogenase

and

Step 2: Enoyl-CoA Hydratase

and

Step 3: 3-hydroxyacly-CoA Dehydrogenase

Answer 8

• Step 1: Acyl-CoA Dehydrogenase
• Step 2: Enoyl-CoA Hydratase
• Step 3: 3-hydroxyacly-CoA Dehydrogenase

Question 9

Step 4: Thiolase

Answer 9

• Energy Totals:
  
  • CoA Synthetase: -2ATP
  • B-oxidation: 1NADH + 1FADH₂ -> 4ATP
  • Acetyl-CoA oxidiation: 3NADH + 1FADH₂ + GTP -> 10 ATP
  • For palmitate (16:0): 7 B-oxidation + 8 acetyl-CoA - 2ATP -> 106ATP

Question 10

Lipolysis/Lipogenesis Control

Answer 10

• Lipogenesis:
  
  • Citrate: feed forward regulation of AA catabolism
  • Insulin: Activates Protein Phosphatase 2A
    
    • Dephosphorylation inhibits Hormone-Sensitive Lipase, activates AA Catabolism
• Lipolysis:
  
  • AMP: Activates AMP-Activated Protein Kinase
    
    • Phosphorylation activates Hormone-Sensitive Lipase, inhibits AA Catabolism
  • Epinephrine: Activates Protein Kinase A
    
    • Phosphorylation activates Hormone-Sensitive Lipase, Inhibits AA Catabolism
  • Glucagon: Activates Protein Kinase A
    
    • Phosphorylation activates Hormone-Sensitive Lipase, Inhibits AA Catabolism

Question 11

Ketone Bodies

Answer 11

• Burning fat efficiently requires glucose

Question 12

Acetyl-CoA

Answer 12

• Central to multiple pathways
• Must be replenished

Question 13

Acetyl-CoA Oxidation

Answer 13

• Requires Glucose
• No TCA cycle = No Acetyl-CoA oxidation
  
  • No Acetyl-CoA oxidation = No Free HS-CoA

Question 14

Ketogenesis

Answer 14

• Ketone Bodies are formed whe oxaloacetate/free HS-CoA have been depleted
  
  • Oxaloacetate is used up by gluconeogenesis
  • Free HS-CoA is used up by utilizing fat or ketogenic amino acids
• Ketogenesis:
  
  • Regenerates Free HS-CoA
  • Supplies energy to tissues, especially heart and brain through ketone bodies
• In Liver and Kidney

Question 15

Ketone Bodies as Energy

Answer 15

• During periods of starvation/low glucose, the brain (and other tissues) can use ketone bodies as an alternative energy source
• Liver cannot use ketone bodies
  
  • lacks the 3-oxoacid CoA transferase enzyme
  • During starvation: Liver oxidizes fatty acids and produces ketone bodies
    
    • Ketone bodies used by other tissues for energy
• Why not just fatty Acids?

Question 16

Ketoacidosis

Answer 16

• Ketone Bodies formed any time when a large portion of the bodies energy is coming from fatty acids and/or ketogenic AA
  
  • Normal: serum [Ketone bodies] ~0.1mM
  • Ketosis: serum [Ketone bodies] >0.5mM (normal condition)
• As Ketone production increases, ketonuria (ketones in urine) balances production
  
  • usually not/barely detectable by urinalysis strips in ketosis
• When Ketone production becomes dysregulated, ketone serum concentration can raise significantly leading to acidosis
  
  • Ketoacidosis: serum [Ketone Bodies] > 1.5 mM (Patholigical)
  • Ketoacidosis leads to reduced serum pH (<7.35) and can be easily measured by significant ketonuria