Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Alice Skoumalová
The liver-introduction
importance in intermediary metabolism and in the
detoxification and elimination of toxic substances
one of the largest organs in the human body
it constitutes only 2-3% of the body mass, it accounts for
20-30% of the total oxygen consumption
Diagram of a hepatocyte
There are approximately 300 billion cells in the liver (80% of them
are hepatocytes)
The hepatocytes are central to the intermediary metabolism of the
body
Functions of the liver
The uptake of nutrients delivered from the digestive tract via the portal vein
The synthesis, storage, interconversion, and degradation of metabolites (metabolism)
The regulated supply of energy-rich intermediates and building blocks for biosynthetic
reactions
The detoxification of harmful compounds by biotransformation
The excretion of substances with the bile, as well as the synthesis and degradation of many
blood plasma constituens
Fighting infections (Kuppfer cells-macrophages)
Liver metabolism
The primary function is the maintenance of sufficient plasma levels of the metabolites
(homeostasis)
Carbohydrate metabolism
Lipid metabolism
Amino acid and protein metabolism
Biotransformations
Liver metabolism
The primary function is the maintenance of sufficient plasma levels of the
metabolites (homeostasis)
Carbohydrate metabolism:
1. The liver takes up glucose and other monosaccharides from the blood plasma
-These sugars are then converted to glucose 6-phosphate and other
intermediates of glycolysis (subsequently, they are either stored as
the reserve carbohydrate glycogen or degraded)
-Another large part is converted into fatty acids
-Only a small fraction is used for the generation of ATP
2. The liver secretes glucose when there is a major decline in the blood glucose level
-This glucose is derived from the glycogen store
-If the glycogen store is already exhausted, glucose can also be synthesized
by gluconeogenesis from lactate, glycerol, or the backbones of amino acids
Lipid metabolism
Amino acid and protein metabolism
Biotransformations
Liver metabolism
The primary function is the maintenance of sufficient plasma levels of the metabolites
(homeostasis)
Carbohydrate metabolism
Lipid metabolism:
1. The liver synthesizes fatty acids from acetate units
-The fatty acids formed are then used for the synthesis of fats and
phospholipids (these are subsequently released into the blood as complexes
with proteins-lipoproteins)
2. The liver can take up fatty acids from the plasma
-The conversion of fatty acids into ketone bodies, which are also excreted
3. The liver also uses acetate units to synthesize cholesterol
-It is then transported to other organs as a constituent of plasma lipoproteins
4. Excess cholesterol is converted into bile acids or excreted with the bile
Carbohydrate metabolism
Lipid metabolism
Amino acid and protein metabolism:
1. The liver controls the amino acid level of the plasma
-It breaks down excess amino acids
-The nitrogen thus released is converted to urea and transported to the
kidneys
-The carbon skeletons of the amino acids enter intermediary metabolism,
where they are consumed either in the synthesis of glucose or in the
production of energy
2. The liver is the site of the synthesis and degradation of most proteins and peptides in
the blood plasma
Biotransformations
Liver metabolism
The primary function is the maintenance of sufficient plasma levels of the metabolites
(homeostasis)
Carbohydrate metabolism
Lipid metabolism
Amino acid and protein metabolism
Biotransformations
1. Steroid hormones and degradation products of the blood pigment
hemoglobin are taken up by the liver
-They are inactivated and converted into highly polar metabolites
2. Drugs, ethanol, and other foreign substances (xenobiotics) are
metabolized by similar reactions
-Preparation for excretion
The role of the liver in nutrition
The tissues are dependent on a constant supply of energy-rich metabolites to
provide energy and as precursors for the synthesis of complex
macromolecules
The liver:
1. It compensates the variation of the level of these fuels in the diet
(buffering organ)
2. It supplies with metabolites (storage organ)
Biochemistry of nutrition:
1. Well-fed (= absorptive state)
-The energy requirements of the tissues are predominantly
met by glucose
The transition between these two states depends on the levels of energy-rich
metabolites in the blood plasma (it is brought about by the joint action of
hormones and signals from the nervous system)
Liver metabolism in the well-fed state
Liver metabolism during starvation
The role of the liver in carbohydrate metabolism
The liver is the most important site for the formation of fatty acids, fats,
ketone bodies, and cholesterol
Absorptive state:
-The liver converts glucose via acetyl-CoA into fatty acids
-The liver can also retrieve fatty acids from lipids supplied with chylomicrons
from the intestine
-The fatty acids are converted into neutral fats and phospholipids, VLDL are
formed (transport of fatty acids to other tissues)
Postresorptive state:
-The adipose tissue releases fatty acids
-Fatty acids are taken up by the liver and oxidatively degraded to acetyl-CoA
-Acetyl-CoA is converted to ketone bodies
Biosynthesis of ketone bodies
Acetyl-CoA (ß-oxidation):
-can be oxidized by the citric acid cycle
-when the acetyl-CoA production exceeds the energy
requirements of the hepatocytes (starvation, diabetes
mellitus) they form ketone bodies (supply other tissues
with energy)
Ketone bodies:
They are released by the liver into the blood, in which they are readily soluble (their
levels are elevated during period of starvation)
3-Hydroxybutyrate and acetoacetate serve as the key metabolites in energy
production (after 1-2 weeks of starvation, the nerve tissue also begins to
utilize ketone bodies as energy sources)
Acetone is exhaled via the lungs
Transformation reactions
Poorly soluble, biologically Either incorporate new functional
active, some toxic groups into apolar compounds, or
Phase alter groups that are already present
I in the molecule
The result is an increase in the
polarity and a decrease in the
biological activity or toxicity of the
substance
The most important reactions:
1. Oxidative reactions: hydroxylation,
epoxide formation, dealkylation,
Transformation deamination
products 2. Reductive reactions
3. Methylation
4. Desulfuration
Biotransformations
Transformation
products
Conjugate formation:
These reactions couple
substrates to highly polar, often
Phase
II negatively charged molecules
The enzymes involved are
transferases
1. Glucuronidation
2. Esterification with sulfate
Conjugate 3. Amidation with glycine and
glutamate
Bile Urine
Cytochrome P450 system
Monooxygenases that contain a heme group
Enzymatic hydroxylation (phase I reactions): drugs, ethanol
Also involved in the biosynthesis of steroid hormones, bile acids, eicosanoids,
and unsaturated fatty acids
Low specificity
Found in the liver, adrenal cortex
Cytochrome P450-dependent
monooxygenases: reactions
The reductive cleavage of molecular oxygen
(one atom is incorporated into the substrate, the
other is released as water)
The reducing equivalents are derived from
NADPH + H+
Cytochrome P450 system
Elevated bilirubin levels in the blood (>10 mg/l); bilirubin may diffuse into
peripheral tissues, giving them a yellow color (jaundice)
Cause:
1. Pre-hepatic: excessive formation of bilirubin by increased
degradation of erythrocytes (icterus neonatus, hemolytic anemia)
2. Hepatic: insufficient processing of bilirubin as a result of
liver defects (hepatitis, liver toxic damage, cirrhosis, hepatic failure)
3. Post-hepatic: by impaired excretion of gall (obstructive
jaundice due to gallstones, inflammation of biliary tract)
Intrahepatic ↑↑(both) ↑ N ↑↑ ↑↑
Posthepatic ↑↑(C) ↑ ↓ ↓ ↓
Biochemical assessment of liver function