Physiology - Liver Function

Learning Objectives

  • Know the five main categories of liver function

  • Describe the role of the liver in blood filtration

  • Describe the role of the liver in metabolism of carbohydrates, fats and proteins, and how these processes are interrelated

  • Describe the role of the liver in vitamin, iron, and copper metabolism

  • Describe the role of the liver in xenobiotic metabolism and detoxification

Five Main Categories of Liver Function

Five Categories: 

  • Blood Filtration

  • Metabolism & detoxification

  • Plasma protein synthesis

  • Bile formation

  • Hormone synthesis (notably IGF-1).

Blood Filtration (With Microanatomy Recap)

Vascular Inflow/Outflow & Lobular Flow:

  • Dual Blood Supply: The liver uniquely receives blood from two sources:

    • Portal Vein: The portal vein supplies about 25% of the blood, which is fully oxygenated blood from the general circulation. This artery delivers oxygen to the liver tissue itself.

    • Hepatic Artery: The hepatic artery supplies the majority of the blood (about 75%) to the liver. This blood is partially deoxygenated but is rich in nutrients absorbed from the small intestine, and it allows the liver to perform its functions related to digestion and detoxification.

  • Blood Flow Pattern: Blood from both vessels mixes and flows through sinusoids (blood-filled spaces that surround the hepatic cells) in the lobules, moving from the periphery (portal triads) inward toward the central vein which merge to form larger collecting veins, eventually draining into the hepatic veins, the inferior vena cava (IVC), and the heart.

Lobular Organisation & Bile Flow:

  • Hepatocyte Architecture: Hepatocytes are arranged in sheaths/lamellae radiating or spiraling from the central vein to the lobule periphery.

  • Bile Direction: Bile produced by hepatocytes flows in the opposite direction to the blood (outward) via bile canaliculi toward bile ducts located in the portal triads, eventually reaching the duodenum or gallbladder.


Sinusoids & Space of Disse - Fenestrated Endothelium: 

  • Fenestrated Endothelium: The sinusoids are lined with fenestrated endothelium (containing large pores).

  • Space of Disse: This fenestration allows plasma, including large proteins, to filter into the Space of Disse (the area between the endothelium and hepatocytes) for efficient exchange with hepatocytes.


Key Non-Parenchymal Cells:

  • Kupffer Cells: These resident macrophages in the sinusoids ingest bacteria and recycle old red blood cells, performing a crucial blood-filtration function.

  • Stellate Cells: Found in the Space of Disse, these cells are specialized for storing Vitamin A.



Macronutrient Metabolism


Nutrient Delivery Overview:

  • Carbohydrates: 

    • Dietary di- and polysaccharides are broken down by digestive enzymes into their monosaccharide products: glucose, fructose, and galactose. 

    • These monosaccharides are then absorbed across the intestinal mucosa and delivered to the liver via the portal vein.

  • Proteins: 

    • Dietary proteins are first broken down by peptidases into amino acids. 

    • Amino acids are absorbed into the capillaries of the intestinal villi, enter the portal circulation, and are delivered directly to the liver via the portal vein.

  • Fats: 

    • Dietary triglycerides are emulsified by bile salts and hydrolyzed by pancreatic lipase into free fatty acids and glycerol. 

    • These products are absorbed into enterocytes, re-esterified into triglycerides, and packaged into chylomicrons. 

    • Chylomicrons enter lacteals and the lymphatic system, pass into the bloodstream, and eventually reach the liver 

      • A small fraction of short- and medium-chain fatty acids can travel directly via the portal vein.



Carbohydrate Metabolism – Glucose Buffer Function: The liver plays a central role in buffering blood glucose under hormonal instruction, particularly from insulin and glucocorticoids produced by the pancreas.

  • Storage When Blood Glucose Is High: 

    • When blood glucose levels are elevated, the liver stores glucose as glycogen through glycogenesis (conversion of glucose into glycogen).

  • Synthesis/Release When Blood Glucose Is Low: 

    • When blood glucose falls, the liver mobilizes glucose through two processes:

      • Glycogenolysis, breaking down glycogen into glucose for release into the circulation.

      • Gluconeogenesis, synthesizing glucose from precursors such as amino acids and glycerol via pyruvate.

    • Additionally, the liver can interconvert fructose and galactose into glucose, and vice versa, providing flexibility in carbohydrate metabolism.

  • Energy Production From Glucose: The liver also uses glucose for its own energy needs. Through glycolysis, glucose is broken down into pyruvate.

    • With adequate oxygen, pyruvate is converted to acetyl-CoA and enters the citric acid cycle to generate ATP.

    • With reduced oxygen availability, the lecture emphasized that the liver can produce ketone bodies as an alternative energy source, including for use by the brain.

  • Conversion of Excess Glucose to Fat: When glucose supply exceeds storage and immediate energy needs, the liver converts glucose into fat. Glycolysis provides acetyl-CoA, which is directed into lipid synthesis pathways. 

    • Importantly, this is a one-way process: fatty acids cannot be converted back into glucose, because the conversion of pyruvate to acetyl-CoA is irreversible.



Fat Metabolism – Roles in the Liver: The liver has multiple roles in fat metabolism, including storage, energy generation, synthesis, and redistribution.

  • Storage of Fat: The liver stores fat within hepatocytes, serving as an energy reserve.

  • Energy from Fat: Fatty acids undergo β-oxidation to form acetyl-CoA.

    • Acetyl-CoA → ATP: Acetyl-CoA can enter the citric acid cycle to generate ATP.

    • Acetyl-CoA → Ketone Bodies: In fasting states or when oxygen availability is low, acetyl-CoA can be diverted into the production of ketone bodies, which serve as an alternative energy source, including for the brain.

  • Synthesis from Fat: The liver synthesises key molecules from fatty acids and triglycerides:

    • Cholesterol: A critical component, with roughly 80% used to produce cholic acid, a precursor for bile salts.

    • Lipoproteins (VLDL, LDL, HDL): Transport vehicles for lipids in the bloodstream.

    • Phospholipids: About 90% of the body's phospholipids (used in cell membranes, myelin sheaths, and lipoproteins) are produced in the liver.

  • Fat Synthesis From Other Macronutrients: The liver can also produce fat from non-lipid sources:

    • Carbohydrates → Fat: From carbohydrates, via glycolysis producing acetyl-CoA that enters lipid synthesis pathways.

      • Fatty acids cannot be converted back into glucose, because the conversion of pyruvate to acetyl-CoA is irreversible.

    • Protein → Fats: From proteins, through amino acid breakdown contributing to lipid precursors.

    • Transported as Lipoproteins: These newly synthesised lipids are exported to adipose tissue in the form of lipoproteins.



Protein Metabolism – Roles in the Liver: The liver regulates protein metabolism by using amino acids for energy, synthesising new molecules, and detoxifying nitrogen.

  • Energy From Amino Acids:

    • Transamination: Involves transferring amino groups to form new amino acids and α-keto acids. 

    • Deamination: Removes amino groups, producing ammonia (NH₄⁺) and α-keto acids. 

      • Ammonia is toxic, so the liver rapidly converts it to urea.

      • Urea Excretion occurs mainly via the kidneys (~75%), with the remainder (~25%) excreted through the intestine, as noted in the lecture.

    • Citric Acid Cycle - α-keto acids → ATP: The α-keto acids can enter the citric acid cycle to produce ATP.

  • Synthesis From Amino Acids:

    • Carbohydrate and Fat Generation: Products of deamination can feed into pathways for carbohydrate or lipid synthesis.

    • Amino Acid Synthesis: Through transamination, the liver can produce non-essential amino acids.

    • Plasma Protein Synthesis: The liver produces the majority of plasma proteins, including albumin, clotting factors, and carrier proteins for hormones and metals. 

      • A key exception is that immunoglobulins are not produced by hepatocytes.



Interrelationship of Macronutrient Pathways: Carbohydrate, fat, and protein metabolism are interconnected through shared intermediates. Amino acids (via transamination and deamination), glucose (via glycolysis), and fatty acids (via β-oxidation) can all feed into acetyl-CoA or citric acid cycle intermediates, allowing interconversion of energy substrates.

  • A key exception, emphasised in the lecture, is that fatty acids cannot be converted into glucose, because the conversion of pyruvate to acetyl-CoA is irreversible.



Vitamin Metabolism – Roles of the Liver


Fat-Soluble Vitamin Absorption: Bile acids secreted by the liver are essential for the intestinal absorption of vitamins A, D, E, and K.


Specific Vitamins:

  • Vitamin D: The liver is a key step in the vitamin D biosynthetic pathway. After skin synthesis, vitamin D is hydroxylated in the liver before further activation in the kidney.

  • Vitamin A: Stellate cells in the Space of Disse store vitamin A, supporting normal vision and immune function.

  • Vitamin E: Functions as an antioxidant throughout the body, including protective roles in the liver.

  • Vitamin K: Required for coagulation and bone health. The liver synthesises clotting factors II, VII, IX, and X, all of which are vitamin K–dependent.

  • Vitamin B12: Stored in the liver and essential for DNA synthesis, myelin maintenance, erythropoiesis, and fatty acid/amino acid metabolism.



Iron and Copper Metabolism


Iron Metabolism – The Liver as a Blood Iron Buffer: Iron is essential for haemoglobin and oxygen transport. 

  • Sources: Its sources include dietary intake and recycling of iron from old erythrocytes, particularly through the spleen.

  • Transport & Storage: 

    • Transferrin: In the bloodstream, iron is transported to the liver bound to transferrin. 

    • Ferritin: Within hepatocytes, iron is stored as ferritin (or as hemosiderin when storage is excessive).

  • Release Control: When circulating iron is low, ferritin releases iron back into the blood via transferrin, ensuring supply to tissues. 

    • Hepcidin: Storage and release are regulated by hepcidin, a liver-derived hormone, giving the liver its role as a blood iron buffer.



Copper Metabolism – Roles of the Liver: Copper is an essential trace element required for erythrocyte formation, iron absorption, collagen synthesis, and energy production.

  • Copper Transport: In blood, copper is transported primarily bound to albumin. 

  • Hepatocytes Handling: Hepatocytes take up copper through CTR1 (copper transporter protein 1), after which intracellular chaperone proteins direct its fate:

    • ATP7A: ATP7A routes copper through the trans-Golgi network, where it is incorporated into ceruloplasmin for release into the bloodstream. 

      • ATP7A also facilitates copper excretion into bile when levels are excessive.

    • Metallothionein: Metallothionein provides intracellular storage of copper.

    • COX17: COX17 delivers copper to mitochondria for the biosynthesis of cytochrome c oxidase, a key respiratory enzyme.



Xenobiotic Metabolism and Detoxification


What are Xenobiotics: Xenobiotics are alien substances not produced by the human body. 

  • The liver plays a central role in neutralising and eliminating these compounds.


Cellular Filtration: Kupffer cells in the liver sinusoids remove bacteria arriving from the gut via the portal vein. This contributes to detoxification at the sinusoidal interface before blood re-enters systemic circulation.


Drug Metabolism: Drug detoxification occurs in three key steps

  • Phase I (Functionalisation): Cytochrome P450 enzymes modify drugs through oxidation, reduction, or hydroxylation, making them mildly water-soluble.

  • Phase II (Conjugation): The addition of conjugate groups (e.g., glucuronic acid, sulfate) renders the drug highly water-soluble.

  • Elimination: The modified drug is excreted through urine, plasma, or bile.


Ethanol Metabolism: 

  • Ethanol is metabolised in the liver to acetaldehyde, and then to acetate. 

  • Acetate can be converted to acetyl-CoA, which may be directed into fatty acid synthesis. 

  • These fatty acids are exported to adipose tissue for storage.



Plasma Protein Synthesis, Bile Formation, and Hormone Synthesis


Plasma Protein Synthesis: The liver produces the majority of plasma proteins. These include 

  • Albumin, which maintains oncotic pressure and transports various molecules

  • Coagulation factors

  • Transport proteins for hormones and metals


Note: A notable exception is that immunoglobulins are not produced by hepatocytes.


Bile Formation: Hepatocytes secrete bile, which contains bile acids and salts that are essential for the absorption of fat-soluble vitamins (A, D, E, K). 

  • Bile drains from hepatocytes into canaliculi, flows into the bile ducts, and is then delivered to the duodenum or stored in the gallbladder.


Hormone Synthesis: The liver also contributes to endocrine function by producing hormones, including insulin-like growth factor 1 (IGF-1).