Ketone Bodies

Question 1

Front

Answer 1

Back

Question 2

What happens if oxaloacetate (OAA) is depleted?

Answer 2

• TCA cycle halts (no citrate formation).<br></br>- Acetyl-CoA diverts to ketogenesis → ketone bodies.<br></br>- Fatty acid synthesis stops (no cytosolic acetyl-CoA).

Question 3

Why can’t acetyl-CoA cross the mitochondrial membrane?

Answer 3

No transporter exists for acetyl-CoA. Citrate carries acetyl groups to cytosol instead.

Question 4

Role of the citrate shuttle in fatty acid synthesis

Answer 4

1. Mitochondrial acetyl-CoA + OAA → citrate.<br></br>2. Citrate exits to cytosol.<br></br>3. ATP citrate lyase (ACL) splits citrate → acetyl-CoA (for FAS) + OAA (returns to mitochondria).

Question 5

Clinical consequence of OAA depletion (e.g., diabetes)

Answer 5

• Ketogenesis ↑ (DKA).<br></br>- Fatty acid synthesis ↓.<br></br>- Gluconeogenesis consumes OAA.

Question 6

Enzyme that converts citrate back to acetyl-CoA in cytosol

Answer 6

ATP citrate lyase (ACL). Activated by insulin in fed state.

Question 7

Key difference: Fed vs. fasting state for citrate shuttle

Answer 7

Fed: Insulin ↑ → citrate shuttle active (FAS).<br></br>Fasting: Shuttle off → acetyl-CoA → ketones.

Question 8

Diabetic ketoacidosis (DKA) and OAA

Answer 8

• OAA depleted for gluconeogenesis.<br></br>- Acetyl-CoA → ketones (via HMG-CoA synthase).<br></br>- Results in metabolic acidosis.

Question 9

Mnemonic for citrate shuttle

Answer 9

‘Citrate = Acetyl-CoA’s Lyft to the cytosol!’

Question 10

Drug target in ketogenesis

Answer 10

HMG-CoA synthase (inhibited by hydroxybutyrate in feedback loop).

Question 11

USMLE/PLAB Q: Why does fatty acid synthesis stop in starvation?

Answer 11

No citrate shuttle (OAA depleted for gluconeogenesis → no cytosolic acetyl-CoA).

Question 12

Major source of energy during prolonged starvation (for brain)

Answer 12

ketone bodies

Question 13

Front

Answer 13

Back

Question 14

Organs involved in ketogenesis

Answer 14

Liver (only producer), Brain/heart/muscles (consumers). USMLE Q: Why no ketosis in liver? (Lacks thiophorase).

Question 15

Precursor for ketone bodies

Answer 15

Acetyl-CoA (from β-oxidation of fatty acids).

Question 16

First committed enzyme of ketogenesis

Answer 16

HMG-CoA synthase (mitochondrial). PLAB Q: Starvation → ↑ this enzyme!

Question 17

3 Ketone Bodies

Answer 17

1. Acetoacetate (primary). 2. β-hydroxybutyrate (reduced form). 3. Acetone (spontaneous decarboxylation).

Question 18

Rate-limiting step of ketogenesis

Answer 18

HMG-CoA → Acetoacetate (via HMG-CoA lyase). NEET-PG Q: Deficiency = HMG-CoA lyase deficiency (hypoketotic hypoglycemia).

Question 19

Why ketogenesis happens?

Answer 19

OAA depletion (starvation/DKA) → TCA cycle stalls → acetyl-CoA diverted to ketones.

Question 20

Tissue usage of ketones

Answer 20

Brain (70% fuel in starvation), Heart, Muscles. USMLE Q: RBCs can’t use ketones (no mitochondria)!

Question 21

Enzyme converting β-OHB to acetoacetate

Answer 21

β-hydroxybutyrate dehydrogenase (requires NAD+).

Question 22

Clinical: Diabetic Ketoacidosis (DKA)

Answer 22

• Cause: Insulin deficiency → unopposed lipolysis → excess acetyl-CoA → ketosis.<br></br>- Lab: ↑β-OHB, ↓pH, ↑anion gap. PLAB Q: Smell of acetone breath!

Question 23

Ketone body synthesis vs. cholesterol synthesis

Answer 23

• Same precursor (HMG-CoA) but different compartments: Ketones (mitochondria), Cholesterol (cytosol).

Question 24

Mnemonic for ketone bodies

Answer 24

‘A BAd Situation’:<br></br>- Acetoacetate<br></br>- Beta-hydroxybutyrate<br></br>- Acetone (least abundant).

Question 25

**Why no ketosis in fed state?**

Answer 25

Insulin → ↓lipolysis → acetyl-CoA enters TCA cycle (OAA available).

Question 26

**Diagnostic test for ketones**

Answer 26

Urine dipstick (nitroprusside reacts with acetoacetate, NOT β-OHB). *USMLE Q: DKA may give false-negative if only β-OHB is high!*

Question 27

**HMG-CoA Synthase activation**

Answer 27

- Activated by: Glucagon, fasting.
- Inhibited by: Insulin, malonyl-CoA.

Question 28

**Key difference: Ketolysis vs. Ketogenesis**

Answer 28

Ketolysis: Extrahepatic (brain/heart). Ketogenesis: Liver only.