Ketone Bodies & Eicosanoids

Ketone Bodies & Eicosanoids

KETONE BODIES

Ketone bodies (KB) are water-soluble alternative fuels produced by the liver during states of glucose scarcity (starvation, uncontrolled DM, prolonged exercise). They are exported to extrahepatic tissues (brain, muscle, heart, kidney) where they are used for energy.

Three Ketone Bodies

  • Acetoacetate: The primary ketone body; produced first
  • β-Hydroxybutyrate (3-Hydroxybutyrate): Reduced form; predominant in blood (~75%). Produced by reduction of Acetoacetate using NADH.
  • Acetone: Non-enzymatic decarboxylation of Acetoacetate; exhaled (fruity breath in DKA); not metabolized

Ketogenesis (in Liver Mitochondria)

Occurs when Acetyl-CoA exceeds TCA cycle capacity (OAA is diverted to gluconeogenesis in fasting):

  1. 2 Acetyl-CoA → Acetoacetyl-CoA [Thiolase]
  2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA [HMG-CoA Synthase — rate-limiting for KB]
  3. HMG-CoA → Acetoacetate + Acetyl-CoA [HMG-CoA Lyase]
  4. Acetoacetate → β-Hydroxybutyrate [β-Hydroxybutyrate DH, using NADH]

Ketone Utilization (in Peripheral Tissues)

Liver LACKS Succinyl-CoA Acetoacetate Transferase (Thiophorase) — so it cannot use its own ketones (important for exams!)

  1. β-Hydroxybutyrate → Acetoacetate [β-HB DH]
  2. Acetoacetate + Succinyl-CoA → Acetoactyl-CoA + Succinate [Thiophorase]
  3. Acetoacetyl-CoA → 2 Acetyl-CoA → TCA cycle

Diabetic Ketoacidosis (DKA)

In Type 1 DM: No insulin → uncontrolled lipolysis → massive FFA delivery to liver → overwhelming ketogenesis. KB are organic acids → blood pH drops <7.3 (metabolic acidosis). Features: Kussmaul breathing, fruity breath, vomiting, dehydration, confusion. Life-threatening emergency.

EICOSANOIDS

20-carbon biologically active lipids derived from polyunsaturated fatty acids (mainly Arachidonic acid, C20:4 ω-6). Released from membrane phospholipids by Phospholipase A2. Have very short half-lives (seconds to minutes); act locally (autocrine/paracrine).

Types and Functions

  • Prostaglandins (PG): Produced by most cells. Actions: Inflammation (PGE2, PGI2), vasodilation, fever, pain, bronchoconstriction, protective gastric mucosa (PGE2 inhibits HCl). NSAIDs block COX-1 and COX-2 → inhibit PG synthesis.
  • Thromboxane A2 (TXA2): Produced by platelets. Promotes platelet aggregation and vasoconstriction.
  • Prostacyclin (PGI2): Produced by endothelium. Opposes TXA2: inhibits platelet aggregation, vasodilator. Aspirin: Irreversibly acetylates COX; low-dose aspirin inhibits TXA2 more than PGI2 (platelets lack nucleus → cannot regenerate COX).
  • Leukotrienes (LT): Produced by WBCs, mast cells, via Lipoxygenase pathway. LTC4, LTD4, LTE4 (cysteinyl LTs) = slow-reacting substances of anaphylaxis (SRS-A) → severe bronchoconstriction in asthma. LTB4 → neutrophil chemotaxis. Montelukast blocks leukotriene receptors.

Synthesis Pathway Overview

Arachidonic acid → [via COX] → PGH2 → PGE2, PGI2, TXA2 | [via LOX] → Leukotrienes

Quiz - Exam Preparation Strategy

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