Introduction

The liver is the largest gland in the body weighing about 1.5 Kg in an adult human. Located at the upper right part of the abdominal cavity below the diaphragm (a shelf-like partition separating the thoracic cavity from the abdominal cavity). It has two main lobes right and left. It receives oxygenated blood from the hepatic artery (a branch of the aorta) and nutrient-rich blood flows from the stomach and intestine to the liver through the portal vein. In this topic, we will know more about the various function of the liver.

The central role of the liver

The functional unit of the liver is the liver lobule numbering about 50,000 to 100000. The major and vital functions are:

•  Filtration and storage of blood.
• Metabolism of carbohydrates, proteins, fats, hormones, and foreign chemicals.
• Bile formation.
• Storage of vitamins, iron, and glycogen.
• Synthesis of plasma proteins like albumins and clotting factors like heparin which prevents clotting of blood inside blood vessels.
•  Detoxification of harmful substances like alcohol, and drugs.
• Plays a vital role in immunity.
• Regeneration.

Role of the liver in the metabolism of nutrients

1. Metabolism of glucose

• Glycogenesis – When an excess of glucose from blood is converted into glycogen and stored in liver cells.
• Glycogenolysis – When the body needs glucose it is obtained by hydrolysis of glycogen.
• Glyconeogenesis – When the body needs glucose it is synthesized from amino acids fatty acids or glycerols.

2. Metabolism of proteins

• The breakdown of amino acids releases nitrogen-containing amine groups (NH2 ) which can be toxic to cells. The removal of these amine groups and converting them into harmless products is known as deamination.
• Amine group is first converted into ammonia which is toxic. So it is converted to urea, excreted by the kidney as a component of urine.
• The amine group can also be transferred to make new amino acids by a process called transamination.
• These amino acids so synthesized are non-essential.
• The remaining carbon part of the amino acid is recycled to produce compounds like glucose, ketone bodies, and acetyl Co A that can be oxidized to produce energy.

3.  Metabolism of  fats

• Oxidation of fatty acids to supply energy for other body functions.
• The fat is broken down into fatty acids and glycerols.
• Fatty acids are converted to acetyl coenzyme A  by beta oxidation which enters the citric acid cycle to liberate energy.
• Sometimes the unused acetyl coenzyme A  in the liver is converted to acetoacetic acid which is transported out of the hepatic cells to all body tissues where they are reconverted to acetyl coenzyme A  and oxidized in a similar manner.
• Synthesis of cholesterol, phospholipids, and lipoproteins.
• Synthesis of fats from proteins and carbohydrates is transported to lipoproteins to the adipose tissue to be stored.

Function of the liver in the regulation of blood glucose level

The liver acts as the body’s glucose reservoir and helps to keep circulating blood sugar levels steady and constant in the blood.

• When blood glucose concentration are low the liver is signaled to add glucose to the circulation.
• And when blood glucose concentrations are high the liver and the skeletal muscles are signaled to remove glucose from circulation.
• This is primarily indicated by the hormone Insulin: the main regulator of sugar in the blood and another hormone Glucagon. Both insulin and glucagon are secreted by the pancreatic gland.
• After a carbohydrate meal the blood glucose level rises, insulin production is turned on and glucagon production is turned off.
• Glucose from the bloodstream enters liver cells stimulating the action of an enzyme that converts glucose to glycogen. The liver takes more glucose from the blood than it releases.
• After the meal is digested the blood glucose level falls. The insulin secretion drops and glycogen synthesis stops.
•  When needed for energy the liver breaks down glycogen and converts it into glucose for easy transport to the bloodstream to the cells of the body.

Role of liver in the detoxification

The liver has the ability to detoxify unwanted and harmful chemical agents. These include food additives, food coloration, food preservatives, drugs (sulfonamides, penicillin, ampicillin, paracetamol, and erythromycin), insecticides, and microplastics. Such foreign substances enter the body through various routes.

The foreign compounds are called xenobiotics. These undergo chemical alterations by the body mainly in the liver to give rise to primary metabolites( the products of metabolism). These primary metabolites are further altered and made water-soluble (secondary metabolites ) which are excreted through urine or bile.

Role of the liver in the filtering of harmful compounds

The gut receives numerous bacteria from the regular food and drink intake. These bacteria release numerous toxins. Also, the gut receives many medications, vitamin supplements, and alcohol. These need to be filtered and made less harmful. Then only it can go to the systemic blood circulation(blood circulation between the heart and body parts ).

The hepatic detoxification is done through

Phase I reactions

• Oxidation: This is the primary reaction that leads to the addition of one or more oxygen atoms to the parent drug.
• Reduction: This type of reaction is coupled with secondary enzymatic system NADPH P450 reductase. Aromatic, nitro, azo, and N-oxide compounds are metabolized in this route.
• Hydrolysis: The parent compound is carried out by certain CYP 450, particularly in the case of esters and amides.
• These reactions are mediated by a group of enzyme systems known as cytochrome P 450  or CYP.
• These conversions produce damaging free radicals which are neutralized by antoxidants within the liver.

Phase II reactions

• Conjugation
• Excretion
• The converted chemicals are then attached to chemical substances like Glutathione, sulfate, and glycine  (conjugation reaction).
• This makes the compounds of the phase I reactions water soluble.
• The water-soluble compounds can now be excreted by the body through urine by the kidneys.

Role of the liver in the metabolism of drugs and alcohols

• Drugs are chemically altered by the liver so that the body can excrete them. This alteration is done by CYPs.
• Drugs are metabolized by the CYPs. This can make it less available to the body and is excreted fast from the body.
• The product of certain metabolic detoxification becomes toxins e.g., Acetaminophen is a nontoxic drug, but due to detoxification during phase I it is converted to a hepatotoxic metabolite.
• A group of enzymes –cytochrome P 450 and alcohol dehydrogenase system converts the alcohol to acetaldehyde.
• Acetaldehyde is toxic to the liver cells the enzyme acetaldehyde dehydrogenase converts acetaldehyde to acetate, a nontoxic molecule.
• The acetate produced is either released into circulation or within the liver it is converted to acetyl Co A which in turn is used to produce other molecules like carbon dioxide and water.

 Synthesis of bile

Bile acids are synthesized from cholesterol in the liver.

• Cholesterol in the presence of vitamin C  and other enzymes forms primary bile acids-Cholic acid and Chenodeoxycholic acid.
• Primary bile acid cholic acid is conjugated with glycine and taurine to form glycocholic acid and taurocholic acid respectively.
• Primary bile acid chenodeoxycholic acid is conjugated with glycine and taurine to form glychochenodeoxycholic acid and taurochenodeoxycholic acid.
• In the intestine, the bacterial enzymes present deconjugate primary bile acids to secondary bile acid deoxycholic acid (from cholic acid ) and lithocholic acid (from chenodeoxycholic acid).
• Primary and secondary bile acids are absorbed in the ileum and 98% of absorbed bile acids are returned to the liver via the portal circulation.
• Conjugated bile acids exist as sodium and potassium salts and are hence known as bile salts. These enter the liver through bile.

Role of the Liver in the Synthesis of Protein

• All plasma proteins (albumin, globulin, hepacidin, transferrin)  with the exception of part of gama globulins are formed by hepatic cells.
• Albumins synthesized by liver cells (hepatocytes ) are not stored in the liver, rather they are rapidly excreted into the bile stream, because they play a major role in maintaining the osmotic pressure in the blood.
• When plasma protein levels decrease rapid cell division of liver cells takes place which increases the output of plasma proteins and it continues until it is back to normal levels.
• Fibrinogen, prothrombin, accelerator globulin, and Factors II, VII, IX, and X responsible for the mechanism of blood coagulation are formed in the liver.

Function of the liver in Bile secretion

One of the main functions of the liver is to secrete bile about 600 to 1000 ml per day. The two most  important functions of bile are :

• Plays an important role in fat digestion and absorption – the bile salts in the bile help to emulsify large fat particles of food into minute particles. This increases the surface area for lipase enzymes to act.
• It aids in the absorption of the end products of digested fat through intestinal mucosal membranes.
• Bile serves as a means for the excretion of several important waste products from blood. These include bilirubin as the end product of hemoglobin destruction and excess cholesterol.

Nutrient storage and liver

• The liver has a tendency to store fat-soluble vitamins. Vitamin A is stored in maximum quantity and followed by vitamin D and vitamin B12.
• It plays a major role in the uptake, storage, and maintenance of circulating plasma vitamin A levels.
• Is responsible for the initial activation of Vitamin D by converting vitamin D3 to 25 – 25-hydroxyl vitamin D3. It also synthesizes vitamin D-binding protein.
• Vitamin K is important in the hepatic synthesis of prothrombin.
• Iron is stored in the liver in the form of ferritin.
• Storage of glycogen allows the liver to remove excess glucose from the blood and store it.

Liver and its role in immunity

The liver is an immune tissue. The liver receives a lot of pathogens from the portal vein(veins from the stomach and intestine enter the liver and not the inferior vena cava)   circulation.

• The defense mechanism of the liver mainly depends on a complex network of phagocytic resident macrophages – Kupffer cells.
• These cells produce cytokines (chemical messengers of immune cells in response to antigens secreted by microbes/pathogens) to signal other immune cells of the infection.
• Through the phagocytic activity of the Kupffer cells pathogens are eliminated before entering systemic circulation.
• Also present in the liver are dendritic cells, neutrophils, natural killer cells, B-lymphocytes, and T-lymphocytes which suggest that it plays a major role in immunity.

Role of the liver in cholesterol Regulation and lipid Regulation

• Cholesterol is an essential component of the cell membrane, a precursor for the synthesis of steroid hormones, vitamin D, and bile acid.
• It is also an essential ingredient in the structure of lipoproteins. Lipoproteins are the forms in which lipids in the body are transported.
• Cholesterol is derived from diet, de novo synthesis ( newly synthesized ), and hydrolysis of cholesteryl esters.  The liver and intestine account for about 10% of cholesterol synthesized by the body.
• The synthesis of cholesterol involves five steps
• Formation of mevalonate from acetyl Co A, which arises from lipid, carbohydrate, and protein metabolism. Non–essential fatty acids, trans fatty acids, saturated fats, and refined carbohydrates are general sources of excessive acetyl Co A, which pressurize our body to biosynthesize cholesterol.
• Formation of isoprenoid units from mevalonate by the loss of carbon dioxide.
• Condensation of 6 isoprenoid units form squalene.
• Squalene gives rise to the parent steroid lanosterol.
• Formation of cholesterol from lanosterol.

Fat is synthesized from carbohydrates and proteins primarily in the liver. Glycerol and fatty acids are rejoined to form triglycerides.

• Triglycerides absorbed as free fatty acids are packaged into chylomicrons /liposomes released through the lymphatic system into the blood and binding to hepatocytes.
• The liver processes chylomicron remnants and liposomes into VLDL ( Very low-density lipoprotein ) and LDL(low-density lipoprotein ) .
• Fatty acids synthesized by the liver get converted into triglycerides and are transported into the blood as VLDL.
• In peripheral tissue, lipoprotein lipase converts VLDL to LDL and free fatty acids by removing triglycerides.
• The remaining VLDL then becomes LDL absorbed by LDL receptors.
• LDL is converted into free fatty acid and cholesterol.
• The liver controls serum cholesterol concentration by removal of LDL.
• HDL carries cholesterol from the body back to the liver to be broken down and excreted.  

Function of the liver in the storage and detoxification of irons

• The hepatic cells contain large amounts of a protein called apoferritn which is capable of combining reversibly with iron, when iron is available in body fluids in extra quantities it combines with apoferritin to form ferritin and is stored in this form in hepatic cells until needed. When iron circulating in the body fluids reaches a low level, the ferritin releases iron.
• Protein transferrin plays a crucial role in the transport and homeostasis of iron in the blood. The circulating plasma transferrin level is inversely proportional to the iron load of the body. The higher the concentration of ferritin in the hepatocyte the lower the rate of transferrin synthesis. During iron deficiency liver synthesis of transferrin is significantly stimulated increasing the intestinal absorption of iron.
• Haptoglobin a large glycoprotein binds free hemoglobin in the blood. The haemoglobin-haptoglobin complex is rapidly removed by the liver conserving iron in the body.
• Hemopexin is another protein synthesized by the liver that is involved in the transport of free heme in the blood. It forms a complex with free heme and the complex is removed by the liver.
• Damaged red blood cells are removed by Kupfer cells of the liver and digested by lysosomes to release heme. Microsomal heme oxygenase releases iron from the heme which enters the free iron pool and is stored as ferritin or released into the bloodstream bound to apotransferin.
• Iron is absolutely essential for survival, but iron overload can be severely toxic, especially to the liver where it can cause hemochromatosis( iron overload). So the liver hepatocytes maintain iron homeostasis.

Some diseases associated with the liver

1. Jaundice

It is caused due to large quantities of bilirubin in the extracellular fluids imparting a yellowish coloration to the skin, and eyes.

 2. Hepatitis

It is the inflammation of the liver caused by any of the several viruses. The most common types are A, B, and C. Symptoms include anorexia, nausea, jaundice, and fatigue.

3. Fatty liver

It results due to improper breakdown of fats, obesity, high blood pressure, diabetes, and alcohol intake, the liver becomes inflamed which damages its tissues and the condition is known as steatohepatitis.

4. Cirrhosis of the liver

It is a result of severe damage to the liver. The extensive scar tissue replaces healthy tissue and slows down liver functioning. It interferes with liver functions and leads to liver failure and liver cancer. 

Q&A

1. What are the five main functions of the liver?

Metabolism, storage of blood, Detoxification, Bile formation, Regeneration.

2. What are the seven main functions of the liver?

Metabolism of carbohydrates, fats, and proteins, Bile production and excretion, Storage of glycogen, vitamins, and minerals, synthesis of plasma proteins, clotting factors, detoxification of drugs and alcohols, regulation of fats and cholesterol, storage of minerals like iron and copper.

3. What is the most important function of the liver?

Bile secretion

4. What are the four warning signs of a damaged liver?

Jaundice( yellowing of skin and eye ). Dark urine color, Abdominal pain and discomfort, pale stool color, and vomiting.

Summary

• The liver is located between the digestive tract and general circulation and plays a multifaceted role in the body.
• It helps in the metabolism of carbohydrates, fats, and proteins.
• Actively detoxifies harmful drugs, both exogenous and endogenous (Xenobiotics), and alcohol, and makes it water soluble so as to enable the kidney to remove from the body through urine. It is done in two steps – phase I and phase II reactions.
• It utilizes carbohydrates for the synthesis of cholesterol and fatty acids.
• The liver stores glucose as glycogen and free fatty acids as triglycerides.
• It maintains blood glucose levels during fasting by synthesis of glucose from glycogen- gluconeogenesis.
• The liver breaks down cholesterol to bile acids which facilitate biliary secretion of cholesterol and intestinal absorption of dietary fats and cholesterol.
• The liver is a storehouse of nutrients, vitamins, and minerals like copper and iron,
• It synthesizes various plasma proteins and blood clotting factors, hence it regulates blood clotting.
• Production of cholesterol and special proteins to help carry fats throughout the body.
• Regulation of blood levels of amino acids, which form the building blocks of proteins.
• Processing of hemoglobin for its iron content ( the liver stores iron).
• Conversion of poisonous ammonia to urea ( an end product of protein metabolism) and is excreted in the urine.
• Last but not least the immune cells present in the liver (Kupffer cells) help in resisting infections by removing bacteria from the bloodstream.

References

1. www.ncbi.nlm.nih.gov>pmc
2. Human physiology: The mechanism of body function – Vander, Sherman, Luciano.
3. Essentials of  Anatomy and Physiology – Valeri C et al.

Written By: Ahana Mitra