Triacylglycerol synthesis lecture 4

Overview of Fatty Acids in Human Metabolism

  • Focus on the role of fatty acids in the human body, particularly their synthesis into triglycerols.

Synthesis of Glycerol

  • Glycerol is an essential component of triglycerides and is derived from glucose.
      - Pathway from Glucose to Glycerol:
        - Glucose is converted into dihydroxyacetone phosphate (DHAP), an intermediate of glycolysis.
        - DHAP is then reduced to glycerol 3-phosphate using NADH as the electron source.
        - This conversion occurs primarily in liver and adipose tissue.

Recycling of Glycerol

  • Glycerol can also be recycled from triglycerides.
      - When triglycerides are broken down in adipose tissue, glycerol is released as a free molecule.
      - Adipose tissue cannot utilize glycerol, but the liver can recycle it using glycerol kinase to convert it back to glycerol 3-phosphate.
      - Importance of Other Carbon Sources:
        - Adipose tissue requires glucose or other metabolites that can convert into DHAP to synthesize glycerol 3-phosphate.

Triglyceride Synthesis Pathway

  • Once glycerol 3-phosphate is formed, fatty acids attach to it via fatty acyl-CoA.
      - Fatty acids must be activated through a process that requires two equivalents of ATP:
        - ATP is converted to AMP and pyrophosphate (PPi).
        - PPi is hydrolyzed to two phosphate molecules, totaling two ATP equivalents used.

  • Formation of Phosphatidic Acid:
      - Glycerol 3-phosphate with two fatty acids results in phosphatidic acid.
        - Phosphatidic acid can diverge into two pathways:
          1. Dephosphorylation by the enzyme lipin to produce diacylglycerol (DAG) which can then be converted to triglycerides by adding a third fatty acyl-CoA.
          2. Attachment of a third alcohol (e.g., serine or ethanolamine) to create glycerophospholipids (e.g., phosphatidylserine, phosphatidylethanolamine).

Regulation of Pathways

  • Insulin's Role: Both pathways for triglyceride (triacylglycerol) or phospholipid synthesis require insulin for activation of acetyl-CoA into fatty acids.

  • Cell signals such as growth hormones influence the direction of phosphatidic acid:
      - Growth hormones lead to phospholipid synthesis.
      - Absence of growth factors favors triglyceride storage.

Characteristics of Triglycerides

  • About 75% of fatty acids released from triglycerides are re-esterified to form new triglycerides, representing a futile cycle:
      - Definition of futile cycle: Simultaneous energy use in one direction with no energy requirement in the reverse direction.
      - Minimum energy loss in this cycle is estimated at 6 ATP.

  • Fatty acids remain available in the bloodstream for use by various tissues like muscle and liver.

Hormonal Influence and Glucose Availability

  • The presence of glucagon disrupts the triacylglycerol cycle in adipose tissue, leading to a deficit of glycerol 3-phosphate due to:
      - Adipose tissue's inability to convert glycerol back into glycerol 3-phosphate.
      - Glycerol must be sent to the liver for conversion.

Glyceroneogenesis

  • Glyceroneogenesis: A partial gluconeogenic pathway occurring in adipose tissue that allows conversion of pyruvate into glycerol 3-phosphate without completing gluconeogenesis.
      - This process involves the enzyme PEP carboxykinase, which is regulated in adipose tissue.

  • Differences based on tissue type:
      - In adipose tissue, it controls fatty acid release.
      - In brown adipose tissue, it regulates thermogenesis, utilizing glycerol 3-phosphate for heat production via fatty acid oxidation.

Liver's Contribution

  • The liver synthesizes triglycerides that are packaged into very low-density lipoproteins (VLDL) for distribution to other tissues, particularly adipose tissue.
      - This completes the triglyceride cycle between liver and adipose tissue, with recycled fatty acids returning from the bloodstream.

Sources of Pyruvate in Adipose Tissue

  • In conditions of glucagon presence, lactate is primarily converted into pyruvate for glycerol 3-phosphate synthesis, as glucose availability is low.
      - The conversion process generates NADH.

Cortisol's Influence on Triglyceride Production

  • Cortisol, a glucocorticoid, impacts metabolism by regulating PEP carboxykinase levels:
      - In the liver, cortisol increases PEP carboxykinase, resulting in increased triglyceride production.
      - In adipose tissue, cortisol decreases PEP carboxykinase, leading to decreased triglyceride production, allowing more fatty acids to remain in circulation.

  • Consequences for Metabolism: Elevated fatty acids can lead to insulin resistance and potentially make type 2 diabetes worse.

Therapeutic Approaches: Thiazolidinediones

  • Thiazolidinediones (e.g., Avandia) activate the PPAR gamma receptor, promoting PEP carboxykinase expression in adipose tissue, aiding the conversion of pyruvate to glycerol 3-phosphate:
      - This lowers blood fatty acid levels and increases glucose utilization in muscle.
      - Associated risks with Avandia include increased heart attack incidence, which has led to reduced use despite its benefits in diabetes management.

Energetic Cost of Triglyceride Rebuilding

  • Analyzing the cost of regenerating a triglyceride from glycerol and fatty acids using lactate as a pyruvate source:
      - Steps and Costs:
        1. Lactate to pyruvate = produces NADH.
        2. Pyruvate to oxaloacetate = consumes ATP.
        3. Oxaloacetate to phosphoenolpyruvate = consumes GTP.
        4. Phosphoenolpyruvate to DHAP = consumes ATP and NADH.
        5. DHAP to glycerol 3-phosphate = produces NADH.
        6. Activating three fatty acids (3 to 3 fatty acyl CoA) = consumes six ATP equivalents.
      - Total calculations yield:
        - +1 from NADH
        - -9 from ATP (6 from activations)
        - Final cost = -6.5 ATP for the synthesis of triglycerides from lactate-derived pyruvate in adipose tissue.