Ketone Bodies Metabolism

Question 1

Synthesis of Ketone Bodies

Answer 1

• in liver, in mitochondria
• increased production during fasting, strenous exercise, as a result of high fat-, low- carbohydrate diet, or in untreated diet
• excess acetyl CoA produced from ß oxidation of fatty acids; more than handling capacity of TCA cycle—>excess acetyl CoA converted to KBs
• KBs readily leave liver and enter circulation
• KBs are taken up by non-hepatic tissues such as brain, heart, kidney, skeletal muscle, and intestine

Question 2

Reactions of KB synthesis

Answer 2

1. 2 acetyl CoA–(acetoacetyl CoA thiolase)–>acetoacetyl CoA
2. acetoacetyl CoA + acetyl CoA –(HMG-CoA synthase)–>ß hydroxy-ßmethyl glutaryl CoA (HMG-CoA)
3. HMG-CoA–(HMG-CoA lyase)–>acetoacetate + acetyl CoA
   
   • Acetoacetate–>acetone + CO2 (spontaneous) OR
   • Acetoacetate–(ß hydroxybutyrate dehydrogenase)–>ß hydroxybutyrate

Question 3

KBs utilization

Answer 3

• oxidized in extrahepatic tissues in the mitochondria
  
  • ß hydroxybutyrate + NAD⁺ –(NAD⁺ dependent ß hydroxybutyrate dH)–>acetoacetate
  • dependent upon NAD+/NADH ratio in the matrix
  • during FA oxidation, NAD+/NADH ratio low–> increased synthesis of ß hydroxybutyrate
• Activation of acetoacetate: CoA transferred from succinyl CoA (from TCA cycle):
  
  • acetoacetate + succinyl CoA –(thiophorase)–>acetoacetyl CoA
  • Thiophorase not in liver or RBC–liver can produce KBs but can’t use them
  • brain normally uses glucose for energy, no thiophorase; after 4 days of starvation–>thiophorase in brain induced for KB utilization
• Acetoacetyl CoA + CoASH–acetoacetyl CoA thiolase)–> 2 acetyl CoA

Question 4

HMG-CoA utilization

Answer 4

• ketones and cholesterol can be synthesized from HMG-CoA
• In cytoplasm of liver, HMG-CoA –(reductase)–>cholesterol
• In mitochondria of liver, HMG-CoA–(lyase)–>ketones

Question 5

KB synthesis frLom amino acids

Answer 5

• Ketongenic aa:
  
  • Leucine
  • Lysine
  • Isoleucine
  • Tryptophan
  • Tyrosine
  • Phenylalanine
• ketogenic–>acetoacetyl-CoA/acetyl CoA–>ketone bodies

Question 6

Ketoacidosis

Answer 6

• Normal KB ~1 mg/dL and undetectable in urine
• Abnormal metabolic conditions: 40-100 mg/dL
  
  • diabetes, prolonged starvation, strenous exercise
• KBs are acidic compounds
• Ketoanemia (20 mg/dL) KB in blood
• at level 70 mg/dL, the renal threshold is exceeded–>exceeded in urine (ketonuria)
• ketoacidosis–blood pH below 7.35
• Two major causes of ketoacidosis:
  
  • Diabetic ketoacidosis: results from increased fat metabolism due to a shortage of insulin; type I; coma if untreated
  • Alcoholic acidosis: depleted protein and carbohydrate stores. alcohol inhibits gluconeogenesis–>decreased insulin secretion, increased glucagon–>lipolysis, impaired fatty acid oxidation, and ketogenesis

Question 7

Post-exercise Ketosis

Answer 7

• During exercise, blood flow directed away from liver, intestines, and kidney to the muscles–>increased FA utilization, KB synthesis decreased
• After exercise, resumption of blood flow to liver–>KB synthesis–>transient ketoic condition
• Elevated KBs return to basal level upon meal intake

Question 8

Regulation of ketogenesis

Answer 8

1. Release of FAs from adipose tissue. FA release controlled by HSL regulated by blood plasma insulin/glucagon levels
2. Once FAs enter liver, they can be activated and oxidized, or esterified to TGs.
   
   1. sufficient glycerol-3-P–>TGs
3. Availability of FAs in mitochondria
   
   1. fed condition–>rise in insulin–>ACC activated–>malonyl CoA–>FA synth, inhibit CPT-1, reduced FA oxidation, reduced KB synthesis
   2. starvation–>rise in glucagon–>ACC inactivated–>relieves inhibitory effect of malonyl CoA on CPT-1–>FA oxidation and ketogenesis
4. NADH/NAD+ ratio determines level of OAA in mitochondria. decreased OAA–>KB synthesis