Liver Functions in Healthy Animals

Learning Outcomes

• Describe the structure and function of the liver in healthy animals:
  • Recognize the cellular organization of the liver and its relationship to liver function in healthy animals.
  • Explain the synthesis of bile salts and the production of bile.
  • Explain the structure and function of the gallbladder and biliary (duct) system in healthy animals.
  • List the testable liver enzymes and their roles and locations within the liver.
  • Review the various liver metabolic pathways involved in carbohydrate, lipid, and protein metabolism.
  • Discuss key liver enzymes and their roles in the metabolism of carbohydrates, protein, and lipids.

The Liver: Structure and Function

The Lobule & Sinusoids

• The lobule is the functional unit of the liver, shaped hexagonally.
• Each lobule consists of cords of hepatocytes:
  • Hepatocytes have:
    • Sinusoidal membranes with microvilli facing the sinusoid.
    • Biliary membranes with tight junctions to adjacent hepatocytes.
• In hepatic sinusoids, oxygen-rich blood from the hepatic artery mixes with nutrient-rich blood from the portal vein.
• Portal triads are located at the vertices of the lobules.

Functional Organization of the Liver

• Divided into three zones (metabolic zonation):
  • Zone 1: Most peripheral, best perfused, access to oxygen-rich blood.
  • Zone 2: Pericentral, intermediate perfusion, great regeneration capacity.
  • Zone 3: Farthest from portal triad, lowest perfusion; contains high concentrations of P450 enzymes crucial for drug metabolism.
• Endothelial cells of hepatic sinusoids allow fluid and proteins to leak through, maximizing exchange between hepatocytes and blood.

Key Functions of the Liver

• Digestion Functions:
  • Bile production for fat digestion.
• Metabolic Functions:
  1. Fat Metabolism:
     • Fatty acid synthesis, lipid transport (VLDLs), and ketogenesis.
  2. Carbohydrate Metabolism:
     • Glycogenesis, gluconeogenesis, glycogenolysis, glucose homoeostasis.
  3. Protein Metabolism:
     • Deamination of amino acids, urea formation, plasma protein synthesis, amino acid conversion.
  4. Detoxification/Excretion:
     • Drugs, hormones, bilirubin elimination.
  5. Storage:
     • Vitamins, minerals, trace elements.

Bile Production and Function

Bile Composition and Synthesis

• Bile consists of:
  • Water (95%), bile salts, phospholipids, cholesterol, bicarbonate, proteins, bilirubin, and sodium.
• Bile Salts Synthesis:
  • Synthesized from cholesterol in hepatocytes with cholesterol 7α-hydroxylase as the rate-limiting enzyme.
• Bile salts promote digestion and excretion of waste (bilirubin, excess cholesterol).

Bile Canaliculi and Gallbladder Function

• Bile components are secreted into bile canaliculi via active transport.
• Bile concentrations in the gallbladder through sodium absorption, followed by chloride and water.
• Gallbladder releases bile into the duodenum for fat digestion.

Carbohydrate Metabolism in the Liver

• Key Metabolic Processes:
  • Glycogenesis: Conversion of glucose to glycogen for storage, regulated by insulin.
  • Glycogenolysis: Breakdown of glycogen to glucose during fasting.
    • Conversion requires Glucose-6-Phosphatase, specific to liver cells.
  • Gluconeogenesis: Production of glucose from non-carbohydrate sources during fasting.
    • Main precursors: amino acids, glycerol, lactate.

Lipid Metabolism in the Liver

• Lipogenesis: Synthesis of fatty acids from excess glucose and amino acids, regulated by insulin.
• Lipolysis: Breakdown of triglycerides into free fatty acids (FFAs) and glycerol, occurring during fasting.
• Beta-Oxidation: FFA breakdown in mitochondria to produce energy via Acetyl-CoA.
• Ketone Bodies Formation: During low glucose availability, FFAs are converted into ketones for energy.

Protein and Amino Acid Metabolism

• Amino acids undergo:
  • Transamination: Transfer of amino groups to produce new amino acids.
  • Deamination: Removal of amino groups, producing ammonia and keto-analogues.
• Ammonia is converted to urea for excretion due to its toxicity.

Testable Liver Enzymes

• Important for diagnostic evaluations of liver function:
  • ALT (Alanine Aminotransferase), AST (Aspartate Aminotransferase), LDH (Lactate Dehydrogenase), etc.

Clinical Relevance

• Accumulation of ammonia due to liver failure can lead to Hepatic Encephalopathy, resulting in neurotoxicity and severe neurological symptoms.