coordination of FA and sugar metabolsim

• Irreversible Steps


  Key regulatory points involve enzymes catalyzing irreversible reactions
• Acetyl CoA Carboxylase (ACC)


  • Catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, a committed step in fatty acid synthesis
• Pyruvate Dehydrogenase (PDH)


  • Converts pyruvate to acetyl-CoA, linking glycolysis to the citric acid cycle and fatty acid synthesis
• High Insulin Levels (Fed State)

  Insulin promotes the uptake and storage of glucose, activates ACC, and enhances fatty acid synthesis
• Enzyme Regulation (Fed State)

  • Pyruvate kinase (PK) upregulated
  • Phosphofructokinase II (PFKII) upregulated
  • Pyruvate carboxylase (PC) upregulated
  • Malic enzyme (ME) upregulated
• High Glucagon Levels (Fasted State)

  Glucagon promotes glycogen breakdown and gluconeogenesis, inhibits ACC, and reduces fatty acid synthesis
• In the fasted state, the liver increases gluconeogenesis and ketogenesis to provide glucose and ketone bodies as energy sources
• Acetyl CoA Carboxylase (ACC)


  • Function: Catalyzes the formation of malonyl-CoA from acetyl-CoA, a key regulatory step in fatty acid synthesis
  • Regulation: Activated by insulin (dephosphorylation) and inhibited by glucagon (phosphorylation)
• Pyruvate Dehydrogenase (PDH)


  • Function: Converts pyruvate to acetyl-CoA, a central metabolic intermediate
  • Regulation: Activated by dephosphorylation in response to high insulin levels and inactivated by phosphorylation in response to high glucagon levels
• Fructose 2,6-Bisphosphate (F26BP)


  • Function: Potent allosteric activator of phosphofructokinase-1 (PFK-1) and inhibitor of fructose-1,6-bisphosphatase (FBPase-1), thus regulating glycolysis and gluconeogenesis
  • Regulation: Synthesized and degraded by PFK-2/FBPase-2, a bifunctional enzyme regulated by insulin and glucagon
• Pentose Phosphate Pathway (PPP)

  • Function: Produces NADPH for anabolic reactions (e.g., fatty acid synthesis) and ribose-5-phosphate for nucleotide synthesis
  • Key Enzyme: Glucose-6-phosphate dehydrogenase (G6PD)
• Malic Enzyme (ME)


  • Function: Converts malate to pyruvate, producing NADPH in the process
  • Regulation: Upregulated in the fed state to support fatty acid synthesis
• Xylulose 5-Phosphate (X5P)


  • Function: Activates protein phosphatase 2A (PP2A), which dephosphorylates and activates PFK-2/FBPase-2, enhancing glycolysis
  • Role in Regulation: Acts as a signaling molecule linking carbohydrate metabolism to lipid synthesis
• Pyruvate Kinase (PK)


  • Function: Catalyzes the final step in glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate
  • Regulation: Exists in active (tetramer) and inactive (dimer) forms; activated by insulin and inhibited by glucagon
• ChREBP (Carbohydrate Response Element Binding Protein)


  • Activation: By Xylulose 5-Phosphate (X5P)
  • Function: Promotes the expression of genes involved in glycolysis and fatty acid synthesis
  • Targets: Pyruvate kinase, ACC, and fatty acid synthase (FAS)
• CREB (Cyclic AMP Response Element Binding Protein)

  • Activation: By cyclic AMP (cAMP) in response to glucagon
  • Function: Promotes the expression of gluconeogenic enzymes
  • Targets: Glucose-6-phosphatase and PEP carboxykinase
• SREBP-1c (Sterol Regulatory Element Binding Protein-1c)


  • Activation: By insulin
  • Function: Promotes the expression of glycolytic and lipogenic enzymes
  • Repression: By glucagon
• FOXO1 (Forkhead Box O1)

  • Role: Stimulates gluconeogenic enzymes and suppresses glycolytic enzymes
  • Regulation: Phosphorylation by insulin leads to its inactivation and export from the nucleus
• Advantages of Redundant Control Mechanisms

  • Robustness: Ensures tight regulation of metabolic pathways under varying physiological conditions
  • Flexibility: Allows quick adaptation to changes in nutrient availability and energy demands
• Summary of Key Regulatory Components

  • Insulin
  • Glucagon
  • Irreversible Steps
  • Gene Expression
• Insulin activates pathways for glucose storage and fatty acid synthesis by promoting dephosphorylation of key enzymes
• Glucagon activates pathways for glucose production and fatty acid breakdown by promoting phosphorylation of key enzymes
• ACC catalyzes the first step in fatty acid synthesis, regulated by hormonal signals
• PDH converts pyruvate to acetyl-CoA, linking glycolysis to the citric acid cycle and fatty acid synthesis
• ChREBP, activated by Xylulose 5-Phosphate, promotes glycolysis and fatty acid synthesis
• CREB, activated by glucagon, promotes gluconeogenesis
• SREBP-1c, activated by insulin, promotes glycolysis and fatty acid synthesis
• FOXO1 promotes gluconeogenesis, inhibited by insulin
• The Pentose Phosphate Pathway provides NADPH for anabolic processes
• Malic Enzyme converts malate to pyruvate, generating NADPH
• Posttranslational modifications, such as phosphorylation/dephosphorylation, regulate key enzymes
• Allosteric modulation, such as regulation by metabolic intermediates (e.g., ATP, acetyl-CoA), regulates enzyme activity