Lecture 23: Ketogenesis

Question 1

Acetyl CoA and Ketogenesis

Answer 1

• Fat reserves are source of acetyl CoA and generate more ATP via beta oxidation than glucose alone
• Catabolism of amino acids can produce glucose or acetyl CoA in the liver
• Fat and amino acid catabolism occurs when epinephrine and glucagon(GPCR signaling) dominate
• Acetyl CoA enters CAC but limited oxaloacetate
• Oxaloacetate depleted when glucose levels drop
• Ketogenesis occurs when too much acetyl coA, ketone bodies used as alternate glucose fuel sources

Question 2

Metabolism of amino acids

Answer 2

• Amino acids can also enter metabolic pathways at various points
• Alpha amino group is first removed and metabolized in urea cycle for excretion as ammonia
• Carbon backbone used to make ATP, glucose or ketone bodies
• Non-essential amino acids can be made from intermediate metabolites

Question 3

Amino Acid Metabolism

Answer 3

• Excess amino acid degraded in liver
• Amino acid carbon skeletons used to generate energy entering as pyruvate, acetyl coA, or citric acid intermediates
• Essential amino acids must be obtained from diet due to more complex biosynthetic pathways
• Glucogenic amino acids used to make glucose, while ketogenic amino acids produce acetyl coA and ketone bodies

Question 4

Fates with Acetyl CoA

Answer 4

• Carbs, fats, and amino acids used to make OAA or acetyl coA
• Acetyl CoA used in CAC to make energy
• When not enough OAA or glucose, Acetyl CoA turned into ketone bodies -> ATP

Question 5

3 ketone bodies made in liver

Answer 5

• Beta-hydroxybutyrate and Acetoacetate: used as energy sources but synthesis contributes to acidosis
• Acetone exhaled as waste product
• 3 Acetyl CoAs brought together to generate the 3 different ketone bodies

Question 6

Use of ketone bodies as fuel by brain or other tissues

Answer 6

• Ketone bodies leave liver and enter the bloodstream
• Ketone bodies can cross blood brain barrier
• Tissues can convert them back to acetyl coA to generate energy

Question 7

Ketogenesis

Answer 7

• Fat reserves and catabolism of ketogenic amino acids are huge source of acetyl coA
• Processing of acetyl coA in CAC limited by amount of oxaloacetate present
• When glucose levels drop and acetyl coA levels rise, ketone bodies are made in liver for energy production
• Acetoacetate and beta-hydroxybutyrate used as fuel by brain, heart, muscle, and kidneys
• Acetone is waste product and gives fruit breath symptom
• Over production of acidic ketone bodies can contribute to drop in blood pH and acidosis

Question 8

Ketoacidosis

Answer 8

• Occurs when ketone levels rise in body due to depleted liver glycogen stores and increased acetyl coA(starvation, low carb diets, and diabetes)
• Blood buffering system initially compensates along with H absorption by bone and tissue, as well as renal secretion
• Acidosis occur when bicarbonate is depleted and blood pH drops below 7.35

Question 9

Why is drop in pH bad?

Answer 9

• Protein denaturation: H binds to functional groups, cause unfolding due to non-covalent interactions
• Enzymes become non-functional -> affect active sites -> decrease ATP
• Impaired metabolic pathways

Question 10

Liver Metabolism

Answer 10

• Liver is main supplier of glucose for rest of the body, releasing glucose from glycogenolysis and producing glucose in GNG
• Cholesterol and fatty acid synthesis takes place in liver, releasing them as lipoprotein complexes in the bloodstream
• Fatty acids cant be used by brain for energy, but liver can provide ketone bodies that get converted back to acetyl coA
• Acetyl CoA from fat breakdown and ketogenic amino acids used to make ketone bodies, while glucogenic amino acids used to make glucose
• Liver helps supply important fuel molecules for the body

Question 11

Ketoacidosis in absence of insulin

Answer 11

• No glucose into cells -> OAA drops -> CAC slows -> beta oxidation breaks down fatty acids -> ketone bodies form -> drop in blood pH -> death
• Deep respiration removes CO2 from blood, causing loss of bicarbonate and lack of buffering capability
• Acidosis affects protein structure and function -> lead to death

Question 12

Symptoms of Type 1 Diabetes

Answer 12

• Excreting glucose + ketone bodies
• Decrease ATP production
• Dilute out solutes
• Fat/protein breakdown(cannot use glucose for energy)

Question 13

Effects of Insulin Administration

Answer 13

• Reduced hyperglycemia and ATP levels rise
• Polydipsia(thirst) and polyuria(excessive urination) eliminated due to drop in blood glucose and ketone body formation
• Blood tonicity normalizes, water balance normalizes
• Glycolysis stimulated, while gluconeogenesis/glycogenolysis inhibited
• Fat breakdown inhibited while fat and glycogen synthesis rises