BCH210 - Lecture 23 - Ketogeesis

what are huge sources of acetyl CoA

-fat reserves are a huge source of Acetyl CoA and generate

more ATP via β-oxidation than glucose alone

what can the catabolism of amino acids produce?

-it can produce acetyl CoA and glucose in the liver

when do fat and amino acid occur?

-when epinephrine and glucagon (GPCR signaling) dominate

ketogenesis

-occurs when Acetyl CoA levels rise and can’t be processed in the liver

-occurs in the absence of glucose

ketone bodies

-occurs when Acetyl CoA levels rise and can’t be processed in the liver

-released by the liver into the bloodstream

-are made spontaneously from excess Acetyl CoA when oxaloacetate is in limited supply

-can be converted back to Acetyl CoA for ATP production, when supplemented with glucose from gluconeogenesis

-arises when we don’t have a lot of OAA (when the CAC can’t compensate to break down the rise of fats)

what is the metabolic process of amino acid production?

-the α amino group is first removed and metabolized in the urea cycle for excretion as ammonia

-the carbon backbone is used to make ATP, glucose or ketone bodies

-amino acid carbon skeletons are used to generate energy entering as pyruvate, Acetyl CoA or Citric Acid Cycle intermediates

**non-essential amino acids (AAs the body can produce) can also be made from intermediate metabolites

where is excess AA degraded?

-in the liver

glucogenic AAs

-can be used to make glucose

ketogenic AAs

-produce Acetyl CoA and ketone bodies

essential AAs

-AAs the human body can’t make

-must be obtained from the diet due to a more complex (6-15 steps) biosynthetic pathways

what molecule is needed to generate ATP from Acetyl CoA

-oxaloacetate (enters the CAC)

what are the 3 ketone bodies made in the liver?

1. beta-hydroxybutyrate (doesn’t necessarily have a ketone group, so isn’t necessarily a ketone body)

2. acetoacetate

3. acetone

what is a ketone group?

-is a C=O attached to another C

which ketone bodies are used for energy sources, but their synthesis contributes to acidosis?

-beta-hydroxybutyrate and acetoacetate

→can be used as fuel by the brain, heart, muscle and kidney cells

acetone

-exhaled waste product all due to the breakdown of fats (can be reason for bad breath in the morning)

acidosis

-process of when you have way too many ketone bodies at one time

how are ketone bodies synthesized?

-3 Acetyl CoAs are brought together to generate the 3 different ketone bodies

how are ketone bodies used as fuel but the brain or other tissues?

-ketone bodies leave the liver and enter the bloodstream

-ketone bodies can cross the blood-brain barrier

-tissues (brain, muscle, heart) can convert them back to Acetyl CoA to generate energy

where does OAA come from?

• GNG → glucose → pyruvate

what can D-3-hydroxybutyrate be broken down to?

-it can be broken down to create 2 acetyl CoA (make 20 ATPs for every 1 acetyl CoA = 10ATPs)

what can over production of acidic ketone bodies contribute to?

-the over production of the acidic ketone bodies can, however, contribute to a drop in blood pH and acidosis

keto(acido)sis

-occurs when ketone levels rise in the body due to depleted liver glycogen stores and increased Acetyl CoA (starvation, low carb diets and diabetes)

-catabolic state

-the blood buffering system initially compensates along with H+ absorption by bone and tissue, as well as renal secretion

-H+ + HCO3 (blood buffer system) —→ H2CO3 —→ H2O + CO2 (exhaled)

-this can occur when bicarbonate is depleted (low) and the blood pH drops below 7.35

what is the main supplier of glucose for the rest of the body?

-the liver is the main supplier of glucose for the rest of the body releasing glucose from glycogen breakdown and producing it in gluconeogenesis (GNG)

-it helps supply important fuel molecules for the rest of the body

what processes take place in the liver?

-GNG

-glycogen breakdown

-cholesterol synthesis (releasing them as lipoprotein complexes in the bloodstream)

-fatty acid synthesis

what can’t be use by the brain for energy?

-fatty acids can’t be used by the brain for energy, but the liver can provide ketone bodies that get converted back to Acetyl CoA

ketoacidosis in the absence of insulin

-catabolic state

-glucose levels drop

1. OAA levels drop

2. CAC slows down

3. fatty acids are released (used in beta-ox in the liver to make acetyl CoA)

4. ketone bodies form

5. blood pH drops

6. coma and death results (in some one with type 1 diabetes)

**Acidosis affects protein structure and/or function, and can lead to

unconsciousness, coma and/or death

symptoms of type 1 diabetes

-excess urine (kidneys excrete glucose + ketone bodies)

-dehydrated, increased blood osmolarity

-decreased ATP from glucose, fats

-fat breakdown and beta-oxidation

effects of insulin administration

-reduced hyperglycemia and ATP levels rise.

-polydipsia (extreme thirst) and polyuria (going to the toilet) are eliminated due to a drop in

blood glucose and ketone body formation.

-blood tonicity normalizes, along with water balance.

-glycolysis is stimulated while

gluconeogenesis/glycogenolysis is inhibited.

-fat breakdown is also inhibited while fat and glycogen

synthesis rises (from excess carbon molecules

what is metabolic flux regulated by?

-metabolic flux is regulated by thermodynamics

metabolic flux

-The movement of metabolites through reversible steps is governed by chemical equilibria thermodynamics

-regulated, “irreversible” reactions regulates the channeling through certain pathways vs. diverting to others

-signaling regulates metabolic pathways

-a block in the pathway either via enzyme inhibition, regulation or mutations can affect the entire metabolic network

-pathways are complex; the results don’t always ‘tell’ you what is going on, but a better understanding of the underlying metabolic defectcan help with treatment options