The Mystery of Mammalian Liver
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Mammalian liver: structure and function
The liver is the most vital organ in the mammalian body and performs all important
functions that impact all body systems. The liver has lobular structure and lies in the
abdominal cavity below diaphragm. The circulatory system of the liver is different
from that of other organs. Roughly 75% of the blood entering in liver through the
portal vein is the venous blood returning back from the small intestine, stomach,
pancreas, and spleen. From this portal venous blood all nutrients along with drugs and
other potentially harmful substances are absorbed. The remaining 25% of the arterial
blood received by liver is the oxygenated blood being carried from the pulmonary
system to the liver by the hepatic artery. The blood contents of the hepatic artery as
well as hepatic portal vein empty into sinusoids. Sinusoidal blood moves towards the
central vein of each lobule and empties its content. Hepatic veins carry deoxygenated
blood from liver to the inferior vena cava (Fawcett, 1994; Malarkey et al., 2005).
2.1.1 Architecture of liver
The liver is covered with a connective tissue capsule (Glisson’s capsule) except at a
region where blood vessels and hepatic/bile ducts enter and/or leave the organ.
Branches of the connective tissue extend throughout the liver as septae. This
connective tissue provides a network, support and the highway along which lymphatic
vessels, bile ducts and afferent blood vessels can traverse across the liver. The
parenchyma of the liver divides into small units called lobules with the help of
connective tissue sheet (Bhunchet and Wake, 1998).
These hepatic lobules are the structural unit of the liver. This lobule consists of a
hexagonal arrangement of plates named as hepatocytes, radiating outward from a
central vein (Figure2.1). The portal triad is a triangular area, comprising of a bile duct
and a terminal branch, each, of the hepatic artery and the portal vein (Fawcett, 1994).
The lateral branches of these vessels are confluent with the thin-walled hepatic
sinusoids that are present between the branching hepatic plates/cords (Fawcett, 1994).
Unlike other capillaries, liver sinusoids provide large surface area for the exchange of
metabolites between blood and hepatocytes as sinusoids have their endothelium which lacks the basal membrane. The sub-endothelial space called as the space of Disse or
per sinusoidal space, separates endothelium from the hepatocytes plates (Grisham,1962).
Cells of liver
The hepatocytes are liver parenchymal cells which consist of 60-80% of liver cell
population. Whereas, the cells such as kupffer cells, stellate cells, biliary epithelial
cells, sinusoidal endothelial cells and lymphocytes are non-parenchymal cells and
comprise the rest 20-40% of the liver cell population (Racanelli and Rehermann,
2006).
Hepatocytes compose a major fraction of hepatic cell population. They are
polyhedral in shape, arranged in single-cell cords or plates. These hepatocytes are
linked together via intercellular adhesion complexes and tight junctions. Their one
side faces the persinusoidal space, while the other faces the bile canaliculi and
covered with microvilli (Bioulac-Sage, 2007). Binucleated cells with large polyploid
nuclei are commonly seen in adult liver (Abel T, 2013). Hepatocytes are responsible
for most of the liver functions such as metabolism, detoxification, synthesis, and
storage of nutrients, carbohydrates, fats, and vitamins. They are also involved in
secretory and excretory functions along with other hepatic cells. These functions are
performed by different hepatocytes residing in different zones of hepatic lobules. This
zonation has been correlated with the direction blood flow and help in carrying
metabolites (Duncan et al., 2009). Most of the hepatic toxins cause necrosis and
damage, which varies with different zonal of hepatic lobules. Thus hepatocytes
present in zone near central vein are more prone to the injury in comparison to the
cells near portal triad region (Michalopoulos and DeFrances, 1997).
Kupffer cells are resident macrophages in liver with largest population. They are
attached to the luminal surface of the sinusoidal endothelium (Figure2.1 c)
(McCuskey and McCuskey, 1990). These cells are essential for the phagocytosis of
foreign particles, infecting organism as well as cytokines products (Taub, 2004).
Hepatic stellate cells are located within persinusoidal space of Disse, in the recesses
between hepatocytes. These cells are associated with several functions such as
secretion of cytokines, storage of vitamin A and synthesis of hepatic extracellular
matrix. They gets activated during liver injury and play a key role in progression of fibrosis.
Biliary epithelial cells, line the bile duct in portal triads and are also known as the
cholangiocytes. The connecting duct between bile duct and bile canaliculi (canal of
Hering) along with hepatocytes are also lined by these biliary cells. They are involved
in modifying bile composition by altering solute and water content (Katsuda T, 2013).
Also, it has now become evident that during liver transplantation,
the biliary epithilium is an important target for leucocytes of the graft recipient
(Scholz et al., 1997).
Endothelial cells are largest group of non-parenchymal cells of liver and line the
intrahepatic circulatory vessels of liver and provide a large surface area for nutrient
absorption. They form a pathogenic and selective barrier during separation of
hepatocytes from sinusoidal blood by exchange of molecules (Racanelli and
Rehermann, 2006; Taub, 2004).
Lymphocytes are present every where in the liver parenchymal sinusoids. These
lymphocytes are also a part of innate immune system and selectively rich in NKT
cells and natural killer cells providing defence against invading pathogens (Taub,
2004).
2.1.3 Liver as a secretory organ
Bile salts are required for emulsification of dietary fats prior to their absorption and
digestion. These bile salts are present in bile juice that is produced by the liver and
secreted into duodenum by common bile duct. Many endogenous and exogenous
compounds are known to be metabolized and excreted into bile through liver. Limited
amount of these compounds were reabsorbed in the small intestine and eliminated by
the kidney. For example, recycling of iron while globins chains get catabolized and
their components are reused. However, hemoglobin also contains a porphyrin called
heme that must be eliminated. Heme is converted into free bilirubin inside phagocytic
cells, which is released into plasma and secreted by the liver. It also involved in bile
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The liver is the most vital organ in the mammalian body and performs all important
functions that impact all body systems. The liver has lobular structure and lies in the
abdominal cavity below diaphragm. The circulatory system of the liver is different
from that of other organs. Roughly 75% of the blood entering in liver through the
portal vein is the venous blood returning back from the small intestine, stomach,
pancreas, and spleen. From this portal venous blood all nutrients along with drugs and
other potentially harmful substances are absorbed. The remaining 25% of the arterial
blood received by liver is the oxygenated blood being carried from the pulmonary
system to the liver by the hepatic artery. The blood contents of the hepatic artery as
well as hepatic portal vein empty into sinusoids. Sinusoidal blood moves towards the
central vein of each lobule and empties its content. Hepatic veins carry deoxygenated
blood from liver to the inferior vena cava (Fawcett, 1994; Malarkey et al., 2005).
2.1.1 Architecture of liver
The liver is covered with a connective tissue capsule (Glisson’s capsule) except at a
region where blood vessels and hepatic/bile ducts enter and/or leave the organ.
Branches of the connective tissue extend throughout the liver as septae. This
connective tissue provides a network, support and the highway along which lymphatic
vessels, bile ducts and afferent blood vessels can traverse across the liver. The
parenchyma of the liver divides into small units called lobules with the help of
connective tissue sheet (Bhunchet and Wake, 1998).
These hepatic lobules are the structural unit of the liver. This lobule consists of a
hexagonal arrangement of plates named as hepatocytes, radiating outward from a
central vein (Figure2.1). The portal triad is a triangular area, comprising of a bile duct
and a terminal branch, each, of the hepatic artery and the portal vein (Fawcett, 1994).
The lateral branches of these vessels are confluent with the thin-walled hepatic
sinusoids that are present between the branching hepatic plates/cords (Fawcett, 1994).
Unlike other capillaries, liver sinusoids provide large surface area for the exchange of
metabolites between blood and hepatocytes as sinusoids have their endothelium which lacks the basal membrane. The sub-endothelial space called as the space of Disse or
per sinusoidal space, separates endothelium from the hepatocytes plates (Grisham,1962).
Cells of liver
The hepatocytes are liver parenchymal cells which consist of 60-80% of liver cell
population. Whereas, the cells such as kupffer cells, stellate cells, biliary epithelial
cells, sinusoidal endothelial cells and lymphocytes are non-parenchymal cells and
comprise the rest 20-40% of the liver cell population (Racanelli and Rehermann,
2006).
Hepatocytes compose a major fraction of hepatic cell population. They are
polyhedral in shape, arranged in single-cell cords or plates. These hepatocytes are
linked together via intercellular adhesion complexes and tight junctions. Their one
side faces the persinusoidal space, while the other faces the bile canaliculi and
covered with microvilli (Bioulac-Sage, 2007). Binucleated cells with large polyploid
nuclei are commonly seen in adult liver (Abel T, 2013). Hepatocytes are responsible
for most of the liver functions such as metabolism, detoxification, synthesis, and
storage of nutrients, carbohydrates, fats, and vitamins. They are also involved in
secretory and excretory functions along with other hepatic cells. These functions are
performed by different hepatocytes residing in different zones of hepatic lobules. This
zonation has been correlated with the direction blood flow and help in carrying
metabolites (Duncan et al., 2009). Most of the hepatic toxins cause necrosis and
damage, which varies with different zonal of hepatic lobules. Thus hepatocytes
present in zone near central vein are more prone to the injury in comparison to the
cells near portal triad region (Michalopoulos and DeFrances, 1997).
Kupffer cells are resident macrophages in liver with largest population. They are
attached to the luminal surface of the sinusoidal endothelium (Figure2.1 c)
(McCuskey and McCuskey, 1990). These cells are essential for the phagocytosis of
foreign particles, infecting organism as well as cytokines products (Taub, 2004).
Hepatic stellate cells are located within persinusoidal space of Disse, in the recesses
between hepatocytes. These cells are associated with several functions such as
secretion of cytokines, storage of vitamin A and synthesis of hepatic extracellular
matrix. They gets activated during liver injury and play a key role in progression of fibrosis.
Biliary epithelial cells, line the bile duct in portal triads and are also known as the
cholangiocytes. The connecting duct between bile duct and bile canaliculi (canal of
Hering) along with hepatocytes are also lined by these biliary cells. They are involved
in modifying bile composition by altering solute and water content (Katsuda T, 2013).
Also, it has now become evident that during liver transplantation,
the biliary epithilium is an important target for leucocytes of the graft recipient
(Scholz et al., 1997).
Endothelial cells are largest group of non-parenchymal cells of liver and line the
intrahepatic circulatory vessels of liver and provide a large surface area for nutrient
absorption. They form a pathogenic and selective barrier during separation of
hepatocytes from sinusoidal blood by exchange of molecules (Racanelli and
Rehermann, 2006; Taub, 2004).
Lymphocytes are present every where in the liver parenchymal sinusoids. These
lymphocytes are also a part of innate immune system and selectively rich in NKT
cells and natural killer cells providing defence against invading pathogens (Taub,
2004).
2.1.3 Liver as a secretory organ
Bile salts are required for emulsification of dietary fats prior to their absorption and
digestion. These bile salts are present in bile juice that is produced by the liver and
secreted into duodenum by common bile duct. Many endogenous and exogenous
compounds are known to be metabolized and excreted into bile through liver. Limited
amount of these compounds were reabsorbed in the small intestine and eliminated by
the kidney. For example, recycling of iron while globins chains get catabolized and
their components are reused. However, hemoglobin also contains a porphyrin called
heme that must be eliminated. Heme is converted into free bilirubin inside phagocytic
cells, which is released into plasma and secreted by the liver. It also involved in bile
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