Liver metabolism

• Specialized Metabolic Functions


  • Different tissues in the body have specialized roles in metabolism
  • The liver plays a crucial role in maintaining metabolic homeostasis by processing nutrients, detoxifying substances, and producing key proteins and molecules
• Portal Vein


  Carries nutrients and toxins to the liver
• Hepatocytes


  • Transform nutrients into fuel, detoxify drugs, and have a high turnover rate of enzymes which can adjust according to dietary changes and tissue needs
• Liver Tissue


  • Can regenerate quickly, adapting to changing metabolic conditions
• Glucose Homeostasis


  1. Glycogen synthesis

  2. Gluconeogenesis
• Glucokinase


  Catalyzes the conversion of glucose to glucose-6-phosphate (G6P)
• Glycogen Synthase


  Facilitates glycogen formation from glucose
• Phosphorylase b


  Involved in glycogen breakdown
• Fructose 2,6-Bisphosphate Kinase


  Regulates glycolysis and gluconeogenesis
• Lipid Synthesis


  1. Cholesterol synthesis

  2. Triglyceride synthesis
• HMG-CoA Reductase


  The rate-limiting enzyme in cholesterol synthesis
• Urea Cycle


  Conversion of ammonia, a toxic byproduct of protein degradation, into urea
• Carbamoyl Phosphate Synthase


  Catalyzes the first step in the urea cycle
• Ketone Bodies Production


  During fasting and lipid metabolism
• Acetoacetyl-CoA Thiolase


  Involved in ketone body formation
• Protein Synthesis


  • Products: Albumin, coagulation factors, lipoproteins, and complement proteins
  • Importance: Essential for blood clotting, immune response, and lipid transport
• Bile Synthesis and Secretion

  1. Facilitates fat absorption in the intestine

  2. Components: Bile salts, crucial for emulsifying fats
• Drug and Toxin Metabolism

  Drug metabolization and excretion
• Cytochrome P450 enzymes


  Involved in the detoxification process
• Vitamin Storage


  • Stores lipid-soluble vitamins A, E, and K for use when needed
• GLUT2 Transporter


  Allows passive diffusion of glucose in and out of hepatocytes
• Glucokinase (Hexokinase IV)


  • Higher Km than other hexokinases, not inhibited by glucose-6-phosphate (G6P), ensuring continuous G6P production even at low glucose levels
  • Converts fructose, galactose, and mannose to G6P
• Glucose-6-Phosphate (G6P) Metabolism


  1. Free Glucose: Dephosphorylated by glucose-6-phosphatase for export to other tissues

  2. Glycogen: Synthesized from G6P for storage in the liver

  3. Glycolysis: G6P is converted to pyruvate, leading to ATP production or fatty acid synthesis

  4. Pentose Phosphate Pathway: Produces NADPH (for anabolic reactions) and ribose-5-phosphate (for nucleotide synthesis)
• Glucokinase


  Converts glucose to G6P
• Glycogen Phosphorylase


  Breaks down glycogen into glucose-1-phosphate
• Phosphofructokinase-2/Fructose 2,6-Bisphosphatase (PFK-2/FBPase-2)


  Dual-function enzyme regulating glycolysis and gluconeogenesis
• Amino Acid Metabolism


  1. Protein Synthesis: Used to produce proteins for the liver and other tissues

  2. Hormone and Nucleotide Synthesis: Amino acids are precursors for these molecules

  3. TCA Cycle Intermediates: Amino acids can be converted into intermediates for energy production or gluconeogenesis
• Urea Cycle


  1. Carbamoyl Phosphate Synthesis: The first step where ammonia is converted to carbamoyl phosphate

  2. Citrulline Formation: From ornithine and carbamoyl phosphate

  3. Argininosuccinate Formation: Citrulline combines with aspartate to form argininosuccinate

  4. Arginine Formation: Argininosuccinate is cleaved to form arginine and fumarate

  5. Urea Formation: Arginine is hydrolyzed to produce urea and regenerate ornithine
• Fatty Acid (FA) Metabolism

  1. Liver Lipids: Synthesis for storage or export

  2. FA Oxidation: Produces acetyl-CoA and NADH for ATP production

  3. Ketone Bodies: Produced from acetyl-CoA during fasting or carbohydrate restriction

  4. Cholesterol Synthesis: For cell membranes and steroid hormone production
• Ketone Bodies


  • Components: β-Hydroxybutyrate, acetoacetate, and acetone
  • Usage: Provide energy, especially for the brain and heart during prolonged fasting. Can replace glucose as an energy source when glucose levels are low
• HMG-CoA Reductase


  A target for statin drugs that lower cholesterol levels
• Regulation of Cholesterol Synthesis

  By hormonal signals (insulin promotes synthesis, glucagon inhibits), AMPK (activated by energy stress), and exercise (increases AMPK activity)
• Liver Functions


  • Energy Management: Glucose, Ketones, Fatty Acids
  • Detoxification: Metabolizes and detoxifies drugs and other harmful substances via the cytochrome P450 enzyme system
  • Nutrient Storage: Stores iron and fat-soluble vitamins (A, D, E, K)
  • Metabolic Adaptation: Adjusts its metabolic activities based on the nutritional state of the body (fed vs. fasting states)