Biochemistry II: Fatty Acid Metabolism Quiz

Biochemistry II (PB 503) - Fatty Acid, Triacylglycerol, and Ketone Body Metabolism

• This course covers the metabolism of fatty acids, triacylglycerols, and ketone bodies.
• The outline includes de novo synthesis of fatty acids, triacylglycerol synthesis, lipolysis, the carnitine shuttle, β-oxidation of fatty acids, oxidation of odd-chain fatty acids, ketogenesis, and ketolysis.

I. Fatty Acid and Triacylglycerol Synthesis

• De novo Synthesis of Fatty Acids:

  • Occurs in the fed state (stimulated by insulin).
  • Primary sites include liver and lactating mammary glands; also in adipose tissue to a lesser extent.
  • Location: cytosol.
  • Initial substrate: Acetyl CoA (derived from glucose).
  • Final product: Palmitic acid (palmitate).
  • Requirements: Acetyl CoA, NADPH, CO2, ATP, and biotin.

• Steps of De Novo Synthesis:

  • Step 1: Transport of Acetyl CoA: Acetyl CoA from mitochondria is transported to cytosol via citrate shuttle. Citrate is a high-energy signal. High ATP and high citrate levels enhance the pathway.
  • Step 2: Carboxylation of Acetyl CoA: Acetyl CoA is carboxylated to malonyl CoA by acetyl CoA carboxylase (ACC). ACC is a regulatory enzyme.
  • Step 3: Palmitate Synthesis: Palmitate is synthesized by fatty acid synthase multienzyme complex. 8 acetyl CoA molecules are needed.

• Major Sources of NADPH:

  • HMP shunt (pentose phosphate pathway): Each glucose molecule entering this pathway yields 2 NADPH.H+.
  • Cytosolic malate to pyruvate conversion (by malic enzyme).
  • Cytosolic isocitrate dehydrogenase.

• Regulation of FA Synthesis:

  • Allosteric Regulation: Citrate activates and palmitoyl CoA inhibits acetyl-CoA carboxylase (ACC).
  • Covalent Modification: Insulin dephosphorylates ACC, activating it and thus increasing FA synthesis. Glucagon and epinephrine phosphorylate ACC, inactivating it and thus decreasing FA synthesis. This is a short-term regulation.
  • Hormonal Regulation: Long-term regulation of FA synthesis: Prolonged high-calorie/high-CHO/low-fat diet increases acetyl CoA carboxylase syntheses. Conversely low calorie/low CHO or high fat diet decreases FA synthesis.

II. Fatty Acid and Triacylglycerol Degradation (Lipolysis)

• Lipolysis:

  • Mobilization of stored fats (triacylglycerols or TAGs) in adipose tissue.
  • Occurs as a response to the fasting state.
  • Takes place in the cytosol of adipose tissue.
  • Initial substrate: TAG.
  • Final products: 3 fatty acids and glycerol (for energy production).
  • Note: The energy yield from fat oxidation is 9 Kcal/g compared to 4 Kcal/g for protein and carbohydrate.

• Steps of Lipolysis:

  • Hormone-sensitive lipase (HSL) breaks down TAGs into diglycerides, monoglycerides, and free fatty acids(FFAs)
  • Diglyceride Lipase (HSL) and Monoacylglycerol Lipase (MGL) continues break down to glycerol and FFAs.
  • Regulation: Hormone-sensitive lipase (HSL) is the rate-limiting step. HSL is activated when phosphorylated by PKA in response to glucagon and epinephrine, and inactivated by dephosphorylation when stimulated by insulin.

III. Fate of Glycerol and Free FAs

• Glycerol can be used for gluconeogenesis.
• Fatty acids (FFAs) are transported in the blood bound to albumin and are used for β-oxidation.

IV. β-Oxidation of Fatty Acids

• This is the primary process of fatty acid oxidation.
• Occurs in the mitochondrial matrix of most tissues.
• Fatty acid is first activated to fatty acyl CoA and then transported into the mitochondria. This requires carnitine shuttle for long-chain FAs.
• The cycle involves four steps: Oxidation, Hydration, Oxidation, Thiolysis.
• Each cycle shortens the fatty acyl CoA by 2 carbons and yields 1 FADH2, 1 NADH, and 1 acetyl CoA.
• Calculation of the energy yield considers the acetyl CoA molecules, number of cycles and ATP yield from each cycle. The total ATP yield is significantly greater than the ATP required for fatty acid activation.

V. Oxidation of Odd-Chain Fatty Acids

• Proceeds through beta-oxidation as even chain FAs.
• Eventually produces propionyl CoA, which is metabolized into succinyl CoA and utilized in the TCA cycle.

VI. Ketogenesis

• Overview:
  • Occurs in the liver in response to prolonged fasting/starvation.
  • Location: mitochondrial matrix of the liver.
  • Initial substrate: excess acetyl CoA from fatty acid oxidation.
  • Final product: 3 ketone bodies (acetoacetate, β-hydroxybutyrate, acetone).
• Steps:
  • Acetoacetyl CoA combines with acetyl CoA.
  • HMG-CoA synthase is the rate-limiting enzyme.
  • Acetoacetate is reduced to β-hydroxybutyrate.
  • Acetone can be released from acetoacetate.

VII. Ketolysis

• Overview:
  • Occurs in the mitochondrial matrix of extrahepatic tissues (brain, kidneys, hearts, etc.) during prolonged fasting/starvation or other conditions where glucose is not available or insufficient.
  • In these tissues, ketone bodies are the primary energy source.
• Steps:
  • Ketone bodies are converted into acetyl CoA.
  • Acetyl CoA enters the TCA cycle, providing energy.

VIII. Ketone Bodies and Uncontrolled Diabetes Mellitus

• Diabetic ketoacidosis (DKA):
  • Characterized by elevated ketone bodies in the blood (ketonemia) and urine (ketonuria).
  • Results from insufficient insulin, increasing lipolysis and subsequent ketogenesis.
  • Fruity odor on the breath due to increased acetone.

IX. Cholesterol Synthesis versus Ketogenesis

• The initial steps of cholesterol synthesis and ketogenesis share some reactions (steps 1 and 2), but their subsequent fates differ. HMG-CoA is a key branching point. The pathways differ in location and rate-limiting steps.