Week 8: Ketone Bodies Flashcards
What occurs during the fasting state?
Fatty acids stored at TAG are released from adipose tissue
What is the purpose of Hormone-sensitive lipases?
Cleaves 3 FA’s from TAG
What transports fatty acids to the liver?
Albumin
What happens to fatty acids when they are in the liver?
Fatty acids are oxidized by b-oxidation to generate acetyl-CoA, NADH and FADH2
Do ketone bodies need to have carriers and transporters when in the blood?
No they are considered organic acids so they are soluble in blood
What is needed to make ketone bodies?
Acetyl-CoA
Where are ketone bodies the synthesized?
Synthesized by the liver and to a lesser extent in the kidney cortex and released into the blood
How are ketone bodies used?
Taken up by extrahepatic tissues and are converted back to acetyl-CoA to be used for energy production by feeding into the citric acid cycle
What is ketogenesis?
Ketone body synthesis
When is ketogenesis activated?
During fasting/starving conditions and when carbohydrates become absent or restricted
How long is considered fasting?
4-24 hrs after eating
How long is considered starving?
More than 24 hrs after eating
Where in the body can ketone bodies be a replacement of glucose?
- Cardiac and skeletal muscles
- Kidneys
- Brain needs to adapt
What happens when there is high levels of Acetyl-CoA from b-oxidation?
- OAA goes into gluconeogenesis
2. Acetyl-CoA goes into ketogenesis forming acetoacetate and b-hydroxybutyrate
What are ketone bodies used by after being exported by the liver?
Extrahepatic tissues
Under starving/fasting conditions what is inhibited by increased acetyl-coa from increased b-oxidation?
Pyruvate dehydrogenase
What occurs when pyruvate dehydrogenase complex is inhibited?
CAC is inactivated
Under starving/fasting conditions what is activated by increased acetyl-coa from increased b-oxidation?
Pyruvate carboxylase
What occurs when pyruvate carboxylase is activated?
- Increases oxaloacetate synthesis
- Shunts oxaloacetate toward gluconeogenesis
- Acetyl Co-A enters the CAC only if sufficient oxaloacetate is available
What are the 3 ketone bodies?
- Acetoacetate
- B-hydroxybutyrate
- Acetone
Where does B-oxidation occur?
Mitochondrial matrix
Where in the liver are ketone bodies synthesized?
Mitochondrial matrix
Describe ketone body synthesis.
- Thiolase joins 2 acetyl-CoAs creating acetocetyl-CoA
- With HMG-CoA synthase, another acetyl-coA is fed into acetocetyl-CoA
- HMG-CoA is formed
- HMG-CoA is synthesized into acetoacetate by HMG-CoA lyase by removing an Acetyl-CoA
- Acetoacetate can enter the blood directly or can be reduced to b-hydroxybutyrate
- Spontaneous decarboxylation of acetoacetate produces acetone, which is volatile and is exhaled by the lungs
How does the thiolase reaction occur if it is unfavorable?
Only occurs when acetyl-coA levels are high
What is the rate-limiting step for ketone body synthesis?
Synthesis of HMG-CoA by HMG-CoA synthase
Why is acetone considered metabolically dead?
It is volatile and exhaled by the lungs
What determine acetoacetate and and b-hydroxybutyrate equilibrium?
NAD+/NADH ratio
When would levels of NADH become higher?
During fasting states due to increased B-oxidation
What does CoA-SH do once its expelled from ketogenesis?
- Continues to b-oxidation
- Needed to form activated FA
- Needed for thiolysis catalyzed reaction to generate Acetyl-CoA
What does acetone do once it’s produced?
Exhaled from lungs
What does acetoacetate do once it’s produced?
Sent to extrahepatic tissues to be used for energy production
What does D-b-hydroxybutyrate do once it’s produced?
- Most reduced ketone body
- Sent to extrahepatic tissues to be used for energy production
- Predominate ketone body formed (3:1) since the NAD+/NADH ratio is low during b-oxidation
Which ketone body predominates?
D-b-hydroxybutyrate
In regards to ketone body formation, what is the purpose of the liver during fasting?
The liver increases the conversion of acetyl-CoA to ketone body formation
Why can’t the liver use ketone bodies as fuel?
Lacks thiophorase that is used to breakdown acetoacetate into 2 acetyl-CoA
Where are ketone bodies when exported out of the liver?
To extrahepatic tissues such as the heart, muscles, kidneys, intestines, and brain
What is the purpose of ketolysis?
Use of ketone bodies as fuel by extrahepatic tissues
Describe the steps of ketolysis
- Extrahepatic tissues take in β-hydroxybutyrate from the blood and transport them to the mitochondrial matrix.
- β-Hydroxybutyrate is oxidized back to acetoacetate and is ultimately converted to 2 acetyl-CoA.
- Acetyl-CoAs are oxidized in the CAC
How can amino acids be used to as energy?
Proteins can be degraded into amino acids where it can be converted into ketone bodies
What products can be made by degraded amino acids?
- OAA
- Pyruvate
- a-Ketoglutarate
- Fumarate
- Succinyl-CoA
- Acetyl-CoA
- Acetoacetate
What’s the difference between glucogenic amino acids and ketogenic aminoacids?
- G: Amino acids can be converted into pyruvate or CAC intermediates to generate glucose through gluconeogenesis
- K: Amino acids can be converted to acetyl-CoA or acetoacetyl-CoA feeding into ketogenesis
What are the metabolic adaptations for proteins during prolonged starvation?
- Proteins are degraded into glucogenic and ketogenic amino acids
- Shifting the use of glucose to fatty acids as fuel
- FAs are mobilized from the adipose tissue and used by tissues for energy so that glucose can be reserved for the brain
- Liver converts these FAs to ketone bodies
Describer the regulation of ketone body synthesis
- The supply of fatty acids is increased from TAG breakdown and promotes hepatic ketone body synthesis during fasting.
- Inhibit FA synthesis by inhibiting Malonyl-CoA formation.
- Oxidation of fatty acyl CoA to Acetyl-CoA generates NADH and FADH2 to supply ATP to the liver
- Increased acetyl-CoA levels activate pyruvate carboxylase to divert OAA to gluconeogenesis.
- Acetyl-CoA is diverted from the CAC into ketogenesis
What is the purpose for ketone bodies?
Transports energy sources from the liver to tissues to generate energy
What is ketosis?
High acetyl-CoA levels leads to the production of ketone bodies and overproduction of ketone bodies
What is acidosis?
The lowering of pH in blood
What is ketoacidosis?
Because ketones are organic acids, they are able to ionize and release proteins. The overproduction of ketone bodies can overwhelm the capacity of the blood’s bicarbonate buffering system lowering the blood’s pH
Describe what occurs during diabetic ketoacidosis?
- The lack of insulin, glucose entry into cells is reduced and fatty acids must be used as an energy source
- FA release from adipose tissue is increased in the absence of insulin
- Therefore ketone bodies are overproduced to make energy
What are the advantages of ketone bodies?
- Ketone bodies are water soluble
2. Ketone bodies can be used by the heart, kidney, brain, and muscles during times of starvation.
What are the disadvantages of ketone bodies?
- Ketones do not generate as much energy as the oxidation of fatty acids or glucose.
- Cannot be used as a energy source for the liver.
- Excess ketogenesis can lead to ketoacidosis.
What is the ketogenic diet?
- Having a high fat (70-80%), low carb (5-10%) with adequate protein (10-20%) diet
- Fats become the primary fuel and are metabolized to acetyl-CoA by reducing in take of glucose
- Shifting diet towards ketone bodies metabolism
- Developing ketosis due to fasting from glucose
What are the disadvantages of ketodieting?
- Very hard to maintain
- Fatigue
- Irritability
- Constipation
- Headaches
- Brain Fog
