BCH 441: Liver Metabolism (By )
Introduction:
The liver is strategically interposed between the general circulation and the digestive tract. It receives 20
to 25% of the volume of blood leaving the heart each minute (the cardiac output) through the portal vein (which
delivers absorbed nutrients and other substances from the gastrointestinal tract to the liver) and through the
hepatic artery (which delivers blood from the general circulation back to the liver). Potentially toxic agents
absorbed from the gut or delivered to the liver by the hepatic artery must pass through this metabolically
active organ before they can reach the other organs of the body. The liver’s relatively large size (approximately
3% of total body weight) allows extended residence time within the liver for nutrients to be properly
metabolized as well as for potentially harmful substances to be detoxified and prepared for excretion into the
urine or feces.
Among other functions, therefore, the liver, along with the kidney and gut, is an excretory organ, equipped
with a broad spectrum of detoxifying mechanisms. It has the capacity, for example, to carry out metabolic
conversion pathways as well as secretory systems that allow the excretion of potentially toxic compounds.
Concurrently, the liver contains highly specific and selective transport mechanisms for essential nutrients that
are required not only to sustain its own energy but to provide physiologically important substrates for the
systemic needs of the organism. In addition to the myriad of transport processes within the sinusoidal and
canalicular plasma membrane sheets (see below), intracellular hepatocytic transport systems exist in organelles
such as endosomes, mitochondria, lysosomes, as well as the nucleus. The sequential transport steps carried out
by these organelles include (1) uptake, (2) intracellular binding and sequestration, (3) metabolism, (4) sinusoidal
secretion, and (5) biliary excretion. The rate of hepatobiliary transport is determined, in part, by the rate of
activity of each of these steps. The overall transport rate is also determined by such factors as hepatic blood
flow, plasma protein binding, and the rate of canalicular reabsorption. The various aspects of the major metabolic
processes performed by the liver have been discussed in greater detail elsewhere in this text. These sources are
referred to as the broad spectrum of the liver’s contributions to overall health and disease are described.
I. LIVER ANATOMY
The human liver consists of two lobes, each containing multiple lobules and sinusoids. The liver receives 75%
of its blood supply from the portal vein, which carries blood returning to the heart from the small intestine,
stomach, pancreas and spleen. The remaining 25% of the liver’s blood supply is arterial, carried to the liver by
the hepatic artery. Blood from both the portal vein and hepatic artery empty into a common conduit, mixing their
contents as they enter the liver sinusoids (Fig. 1). The sinusoids are expandable vascular channels that run
through the hepatic lobules. They are lined with endothelial cells that have been described as “leaky” because, as
blood flows through the sinusoids, the contents of the plasma have relatively free access to the hepatocytes,
which are located on the other side of the endothelial cells.
Fig. 1: Schematic view of liver anatomy
The liver is also an exocrine organ, secreting bile into the biliary drainage system. The hepatocytes secrete
bile into the bile canniculus, whose contents flow parallel to that in the sinusoids but in the opposite direction.
The canniculi empty into the bile ducts. The lumina of the bile ducts then fuse, forming the common bile duct.
The common duct then releases bile into the duodenum. Some of the liver’s effluent is stored in the gallbladder
and discharged into the duodenum postprandially to aid in digestion.
Page | 1
, The entire liver surface is covered by a capsule of connective tissue that branches and extends throughout
the liver. This capsule provides support for the blood vessels, lymphatic vessels, and bile ducts that permeate the
liver. In addition, this connective tissue sheet subdivides the liver lobes into the smaller lobules.
II. LIVER CELL TYPES
The primary cell type of the liver is the hepatocyte. Hepatocytes, also known as the hepatic parenchymal
cells, form the liver lobules. Eighty percent of the liver volume is composed of hepatocytes, but only 60% of the
total number of cells in the liver are hepatocytes. The other 40% of the cells are the nonparenchymal cells,
which constitute the lining cells of the walls of the sinusoids. The lining cells comprise the endothelial cells,
Kupffer cells, and hepatic stellate cells. In addition, intrahepatic lymphocytes, which include pit cells (liver-
specific natural killer cells), are also present in the sinusoidal lining.
A. Hepatocytes
The hepatocyte is the cell that carries out the many functions of the liver. Almost all pathways of
metabolism are represented in the hepatocyte and these pathways are controlled through the actions of
hormones that bind to receptors located on the plasma membrane of their cells. Although normally quiescent cells
with low turnover and a long life span, hepatocytes can be stimulated to grow if damage occurs to other cells in
the liver. The liver mass has a relatively constant relationship to the total body mass of adult individuals.
Deviation from the normal or optimal ratio (caused, for example, by a partial hepatectomy or significant hepatic
cell death or injury) is rapidly corrected by hepatic growth caused by a proportional increase in hepatocyte
replication.
B. Endothelial Cells
The sinusoidal endothelial cells constitute the lining cells of the sinusoid. Unlike endothelial cells in other
body tissues, these cells contain fenestrations with a mean diameter of 100 nm. They do not, therefore, form a
tight basement membrane barrier between themselves and the hepatocytes. In this way, they allow for free
diffusion of small molecules to the hepatocytes but not of particles the size of chylomicrons (chylomicron
remnants, however, which are smaller than chylomicrons, do have free passage to the hepatocyte). The
endothelial cells are capable of endocytosing many ligands and also may secrete cytokines when appropriately
stimulated. Because of their positioning, lack of tight junctions, and absence of a tight basement membrane, the
liver endothelial cells do not present a significant barrier against the movement of the contents of the sinusoids
into hepatocytes. Their fenestrations or pores further promote the free passage of blood components through
this membrane into the liver parenchymal cells.
C. Kupffer Cells
These cells are located within the sinusoidal lining. They contain almost one quarter of all the lysosomes of
the liver. The Kupffer cells are tissue macrophages with both endocytotic and phagocytic capacity. They
phagocytose many substances such as denatured albumin, bacteria, and immune complexes. They protect the liver
from gut-derived particulate materials and bacterial products. On stimulation by immunomodulators, these cells
secrete potent mediators of the inflammatory response and play a role in liver immune defense through the
release of cytokines that lead to the inactivation of substances considered foreign to the organism. The Kupffer
cells also remove damaged erythrocytes from the circulation.
D. Hepatic Stellate Cells
The stellate cells are also called perisinusoidal or Ito cells. There are approximately 5 to 20 of these cells
per 100 hepatocytes. The stellate cells are lipid-filled cells (the primary storage site for vitamin A). They also
control the turnover of hepatic connective tissue and extracellular matrix and regulate the contractility of the
sinusoids. When cirrhosis of the liver is present, the stellate cells are stimulated by various signals to increase
their synthesis of extracellular matrix material. This, in turn, diffusely infiltrates the liver, eventually
interfering with the function of the hepatocytes.
E. Pit Cells
The hepatic pit cells, also known as liver-associated lymphocytes, are natural killer cells, which are a defense
mechanism against the invasion of the liver by potentially toxic agents, such as tumor cells or viruses.
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Introduction:
The liver is strategically interposed between the general circulation and the digestive tract. It receives 20
to 25% of the volume of blood leaving the heart each minute (the cardiac output) through the portal vein (which
delivers absorbed nutrients and other substances from the gastrointestinal tract to the liver) and through the
hepatic artery (which delivers blood from the general circulation back to the liver). Potentially toxic agents
absorbed from the gut or delivered to the liver by the hepatic artery must pass through this metabolically
active organ before they can reach the other organs of the body. The liver’s relatively large size (approximately
3% of total body weight) allows extended residence time within the liver for nutrients to be properly
metabolized as well as for potentially harmful substances to be detoxified and prepared for excretion into the
urine or feces.
Among other functions, therefore, the liver, along with the kidney and gut, is an excretory organ, equipped
with a broad spectrum of detoxifying mechanisms. It has the capacity, for example, to carry out metabolic
conversion pathways as well as secretory systems that allow the excretion of potentially toxic compounds.
Concurrently, the liver contains highly specific and selective transport mechanisms for essential nutrients that
are required not only to sustain its own energy but to provide physiologically important substrates for the
systemic needs of the organism. In addition to the myriad of transport processes within the sinusoidal and
canalicular plasma membrane sheets (see below), intracellular hepatocytic transport systems exist in organelles
such as endosomes, mitochondria, lysosomes, as well as the nucleus. The sequential transport steps carried out
by these organelles include (1) uptake, (2) intracellular binding and sequestration, (3) metabolism, (4) sinusoidal
secretion, and (5) biliary excretion. The rate of hepatobiliary transport is determined, in part, by the rate of
activity of each of these steps. The overall transport rate is also determined by such factors as hepatic blood
flow, plasma protein binding, and the rate of canalicular reabsorption. The various aspects of the major metabolic
processes performed by the liver have been discussed in greater detail elsewhere in this text. These sources are
referred to as the broad spectrum of the liver’s contributions to overall health and disease are described.
I. LIVER ANATOMY
The human liver consists of two lobes, each containing multiple lobules and sinusoids. The liver receives 75%
of its blood supply from the portal vein, which carries blood returning to the heart from the small intestine,
stomach, pancreas and spleen. The remaining 25% of the liver’s blood supply is arterial, carried to the liver by
the hepatic artery. Blood from both the portal vein and hepatic artery empty into a common conduit, mixing their
contents as they enter the liver sinusoids (Fig. 1). The sinusoids are expandable vascular channels that run
through the hepatic lobules. They are lined with endothelial cells that have been described as “leaky” because, as
blood flows through the sinusoids, the contents of the plasma have relatively free access to the hepatocytes,
which are located on the other side of the endothelial cells.
Fig. 1: Schematic view of liver anatomy
The liver is also an exocrine organ, secreting bile into the biliary drainage system. The hepatocytes secrete
bile into the bile canniculus, whose contents flow parallel to that in the sinusoids but in the opposite direction.
The canniculi empty into the bile ducts. The lumina of the bile ducts then fuse, forming the common bile duct.
The common duct then releases bile into the duodenum. Some of the liver’s effluent is stored in the gallbladder
and discharged into the duodenum postprandially to aid in digestion.
Page | 1
, The entire liver surface is covered by a capsule of connective tissue that branches and extends throughout
the liver. This capsule provides support for the blood vessels, lymphatic vessels, and bile ducts that permeate the
liver. In addition, this connective tissue sheet subdivides the liver lobes into the smaller lobules.
II. LIVER CELL TYPES
The primary cell type of the liver is the hepatocyte. Hepatocytes, also known as the hepatic parenchymal
cells, form the liver lobules. Eighty percent of the liver volume is composed of hepatocytes, but only 60% of the
total number of cells in the liver are hepatocytes. The other 40% of the cells are the nonparenchymal cells,
which constitute the lining cells of the walls of the sinusoids. The lining cells comprise the endothelial cells,
Kupffer cells, and hepatic stellate cells. In addition, intrahepatic lymphocytes, which include pit cells (liver-
specific natural killer cells), are also present in the sinusoidal lining.
A. Hepatocytes
The hepatocyte is the cell that carries out the many functions of the liver. Almost all pathways of
metabolism are represented in the hepatocyte and these pathways are controlled through the actions of
hormones that bind to receptors located on the plasma membrane of their cells. Although normally quiescent cells
with low turnover and a long life span, hepatocytes can be stimulated to grow if damage occurs to other cells in
the liver. The liver mass has a relatively constant relationship to the total body mass of adult individuals.
Deviation from the normal or optimal ratio (caused, for example, by a partial hepatectomy or significant hepatic
cell death or injury) is rapidly corrected by hepatic growth caused by a proportional increase in hepatocyte
replication.
B. Endothelial Cells
The sinusoidal endothelial cells constitute the lining cells of the sinusoid. Unlike endothelial cells in other
body tissues, these cells contain fenestrations with a mean diameter of 100 nm. They do not, therefore, form a
tight basement membrane barrier between themselves and the hepatocytes. In this way, they allow for free
diffusion of small molecules to the hepatocytes but not of particles the size of chylomicrons (chylomicron
remnants, however, which are smaller than chylomicrons, do have free passage to the hepatocyte). The
endothelial cells are capable of endocytosing many ligands and also may secrete cytokines when appropriately
stimulated. Because of their positioning, lack of tight junctions, and absence of a tight basement membrane, the
liver endothelial cells do not present a significant barrier against the movement of the contents of the sinusoids
into hepatocytes. Their fenestrations or pores further promote the free passage of blood components through
this membrane into the liver parenchymal cells.
C. Kupffer Cells
These cells are located within the sinusoidal lining. They contain almost one quarter of all the lysosomes of
the liver. The Kupffer cells are tissue macrophages with both endocytotic and phagocytic capacity. They
phagocytose many substances such as denatured albumin, bacteria, and immune complexes. They protect the liver
from gut-derived particulate materials and bacterial products. On stimulation by immunomodulators, these cells
secrete potent mediators of the inflammatory response and play a role in liver immune defense through the
release of cytokines that lead to the inactivation of substances considered foreign to the organism. The Kupffer
cells also remove damaged erythrocytes from the circulation.
D. Hepatic Stellate Cells
The stellate cells are also called perisinusoidal or Ito cells. There are approximately 5 to 20 of these cells
per 100 hepatocytes. The stellate cells are lipid-filled cells (the primary storage site for vitamin A). They also
control the turnover of hepatic connective tissue and extracellular matrix and regulate the contractility of the
sinusoids. When cirrhosis of the liver is present, the stellate cells are stimulated by various signals to increase
their synthesis of extracellular matrix material. This, in turn, diffusely infiltrates the liver, eventually
interfering with the function of the hepatocytes.
E. Pit Cells
The hepatic pit cells, also known as liver-associated lymphocytes, are natural killer cells, which are a defense
mechanism against the invasion of the liver by potentially toxic agents, such as tumor cells or viruses.
Page | 2
