Fatty Acid Oxidation

Question 1

Reason why fatty acids are preferred fuel source for liver, heart, and muscle at all times

Answer 1

• More reduced than proteins or carbohydrates
  
  • More energy can be extracted when oxidized
  • Hydrophobic = not as hydrated as proteins or carbohydrates
    
    • Explains why fatty acids evolutionarily chosen over glycogen for most significant energy store in body
• In fasting state, most energy for skeletal and cardiac muscle contraction comes from oxidation of fatty acids released from adipose tissue
• Yield from complete oxidation of fatty acid –> CO2 and H2O = 9kcal/g of fat
  
  • Compared to 4kcal/g of protein or carbohydrate

Question 2

Reasons why fatty acids are major energy source for all tissues in starvation conditions

Answer 2

• Starvation conditions: fatty acids released from triacylglycerols by hormone-sensitive lipases
• FFAs released into blood, transported to liver, muscle, etc. by association with albumin
• Fatty acids then degraded by beta-oxidation
• Fatty acids not delivered to brain because they cannot cross BBB

Question 3

3 stages of fatty acid oxidation (beta-oxidation)

Answer 3

1. Release of fatty acid from TAG
   
   • Initiated by hormone-sensitive lipase – removes fatty acid from from carbon 1 and/or 3 of TAG
     
     • HSL activated by epinephrine
2. Transport into mitochondrial matrix
   
   • Fatty acid group transferred temporarily to carnitine (catalyzed by CPT) because Acetyl CoA cannot enter mitochondrial matrix
   • Major regulatory step in fatty acid oxidation
   • Inhibited by malonyl CoA (intermediate of synthesis)
3. Repeated cycles of oxidation
   
   • Beta-oxidation: major pathway
   • So named because b-carbon gets oxidized
   • Each cycle of oxidation has 4 steps –> yield 2 carbon acetyl CoA, 1 FADH2, 1 NADH

Question 4

Beta oxidation pathway: 4 steps, critical intermediates, enzymes, cofactors

Answer 4

1. Acyl CoA dehydrogenase
   
   • Located in mitochondrial matrix
   • Oxidizes acyl CoAs
   • 4 forms of enzymes: short (4-8), medium (8-14), long (12-18), and very long, carbon chains
   • Uses FAD and introduces trans double bond
   • Genetic defects in all 4 enzymes exist
     
     • Causes severe hypoglycemia provoked by fasting
     • MCAD (medium chain enzyme) deficiency is cause of some cases of SIDS
2. Enoyl CoA hydratase
   
   • Adds water across trans double bond created in #1
3. beta-hydroxy CoA dehydrogenase
   
   • Oxidizes hydroxyl generating b-keto-acyl-CoA and NADH from NAD
4. Thiolase
   
   • Releases acetyl CoA, transfers fatty acid shortened by two carbons to CoA-SH for another round of oxidation
   • Malonyl CoA inhibits CPT and FA breakdown/beta oxidation

Question 5

Fatty acid degradation vs. synthesis (summary) – this is a table from the slides, you probably don’t have to know all of it but maybe the general idea.

Answer 5

ITS GOOD REVIEW SHUT UP

Question 6

3 ketone bodies

Answer 6

1. Acetoacetate
2. 3-hydroxybutarate
3. Acetone
   
   • derived from spontaneous degradation of acetoacetate

Question 7

Synthesis and use of ketone bodies

Answer 7

• All water-soluble, transportable forms of acetyl units
• When fatty acid oxidation occurs in liver, some acetyl units enter TCA cycle for eventual ATP generation; others used to produce ketone bodies
• Production of ketone bodies by liver increases during fasting/very low carb diets

Question 8

Result of overproduction of ketone bodies

Answer 8

Metabolic ketoacidosis

Question 9

Surplus of ketone bodies in type 1 diabetes

Answer 9

• Extremely high levels released during periods of extreme metabolic stress
• Most commonly seen in type 1 diabetics when insulin levels drop too low (failure to take insulin, illness, stress, etc.)
• Hormone-sensitive lipase highly activated –> releases fatty acids from adipose –> liver generates/releases high levels of ketone bodies
• Ketone bodies (moderately strong acids) –> lower blood pH –> metabolic ketoacidosis
• Sometimes can smell acetone on patient’s breath