Liver Physiology Lecture Notes

Introduction

• Physiology of liver functions in metabolism
• Focus on the liver in fed and fasting states
• The liver's multifunctionality likened to expressing love: "I love you with all my liver"

Fed State Metabolism

Carbohydrates

• Portal blood delivers nutrient-rich blood (esp. glucose) to liver cells via GLUT2 transporters
• Key pathways:
  1. Glycogenesis: glucose → glycogen (storage form)
  2. Pentose Phosphate Pathway: glucose → ribose-5-phosphate + NADPH (for fatty acid synthesis, nucleotide metabolism, antioxidant reactions)
  3. Glycolysis: glucose → pyruvate → Acetyl-CoA → Krebs cycle → ATP
  4. Fatty Acid Synthesis: excess Acetyl-CoA → fatty acids → glycerol → triglycerides

Amino Acids

• Amino acids enter liver cells via sodium-dependent cotransport
• Main roles:
  1. Protein synthesis
  2. Excess amino acids → Acetyl-CoA → Fatty acids → Triglycerides

Fats

• Transported to the liver as chylomicrons carrying triglycerides and cholesterol
• Key processes:
  1. Triglycerides → fatty acids + glycerol → triglycerides
  2. Cholesterol → cholesterol esters (storage), bile acids, VLDL (distributes cholesterol and triglycerides to tissues)
  3. VLDL converts to IDL and LDL, returns to liver or distributed to peripheral tissues (including HDL for reverse cholesterol transport)

Fasting State Metabolism

Glucose Metabolism

• Stimulated by low blood glucose → release of glucagon, other hormones (e.g., cortisol, growth hormone)
• Key pathways:
  1. Glycogenolysis: glycogen → glucose
  2. Gluconeogenesis: amino acids, glycerol, lactic acid → glucose
  3. Urea Cycle: amino acid breakdown produces ammonia → urea (excreted by kidneys)
  4. Beta-Oxidation: fatty acids → Acetyl-CoA → Krebs cycle or → ketone bodies (Acetoacetate, Beta-Hydroxybutyrate)

Liver as a Protein Factory

Main Proteins Produced

• Albumin: maintains osmotic pressure, accounts for 60% of plasma proteins
• Decreased albumin in liver damage (e.g., hepatitis, cirrhosis)
• Globulins (alpha & beta): transport proteins for steroid hormones, trace minerals (e.g., ceruloplasmin for copper, transferrin for iron, retinol-binding protein for vitamin A)
• Clotting Proteins: Factor 2, 7, 9, 10, protein C&S (vitamin K dependent), fibrinogen (factor 1)
• Anti-clotting Proteins: Plasminogen (converted to plasmin), Antithrombin III (deactivates clotting factors)
• Hormones: Thrombopoietin (platelet synthesis), IGF-1 (growth hormone), Angiotensinogen (blood pressure regulation)
• Immune Proteins: Complement proteins (C1-C9), C-reactive peptide (inflammation marker)
• Apo Proteins: Apo A, B, C, E (lipoprotein metabolism)

Liver Storage Functions

Vitamins

• Fat-soluble vitamins: A, D, E, K
  • Vitamin D: Skin synthesis from 7-dehydrocholesterol → 25-hydroxycholecalciferol (liver) → 1,25-dihydroxycholecalciferol (kidneys) for calcium absorption
  • Vitamin K: Required for activation of clotting factors; inhibited by drugs like Warfarin
  • Vitamin A: Stored as retinol in stellate cells, important for vision and skin
  • Vitamin E: Antioxidant, incorporated into VLDLs
• Vitamin B12: Transported by trans cobalamin 2, essential for erythropoiesis and DNA synthesis

Trace Minerals

• Iron: Carried by transferrin, stored in liver as ferritin/hemosiderin; excess regulated by hepcidin
• Copper: Bound to albumin, stored in liver, excreted into bile; deficiency/mutation in ATP7B leads to Wilson's disease