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DEFINITIONS
•Glycolysis: The catabolic pathway by which a molecule of glucose is
broken down into two molecules of pyruvate.
•Gluconeogenesis: The biosynthesis of a carbohydrate from simpler, non
carbohydrate precursors such as oxalacetate or pyruvate.
•Glycogen synthesis: The synthesis of glycogen from glucose.
•Glycogenolysis: The controlled breakdown of glycogen and release of
glucose.
Gluconeogenesis
Piruvate
Glycogen synthesis
GLUCOSE
Glycolysis
Glycogen
Glycogenolysis
Nature of fuels provided to the liver by the intestine
13-15% from Proteins (100 g)
40% from Carbohydrates (300 g)
Diet of 3000 kilocalories/day
40% from Fats (130 g)
7% from Ethanol (30g)
Nature of fuels provided to the liver by the intestine
•The liver plays a central processing and distributing role in metabolism and furnishes all
the organs and tissues with an appropriate mix of nutrients via the blood stream.
Different Nutrients
Monomeric subunits
Digestion
Carbohydrates
Sugars
Proteins
Aminoacids
Lipids
Triacylglycerols
Absorption
Blood
Blood
Blood
Lymphatic
System
Tissues
Liver
Different
FUELS
Liver
Adipose Tissue
Glucose
Metabolites
Digestion
Liver
Acetoacetate
Storage lipids
Creatine
CARBOHYDRATES
•Glucose, fructose, galactose and manose, all absorbed from the small intestine, and are
converted in glucose-6-phosphate.
Liver Glycogen
Glucose-6-phosphate is
1.-converted in glucose and exported
2.-converted into glycogen
3.-oxidized for energy production via glycolisis.
4.-degraded into acetyl-CoA, which serves as
precursor for the synthesis of lipids.
5.-substrate of the pentose phosphate pathway,
yielding ribose-5 phosphate, a precursor in
nucleotide synthesis.
AMINO ACIDS
Amino acids act as precursors for protein synthesis in hepatocytes.
1.-The liver constantly renews its own proteins, and is also the site of biosynthesis of most of
the plasma proteins of the blood.
2.-Amino acids may pass from the liver via the
blood to other organs.
3.-certain amino acids are precursors in the
biosynthesis of;
-nucleotides
-hormones
-other nitrogen compounds
4.-Amino acids not needed as a biosynthetic
precursors are degraded to yield acetyl-CoA
and citric acid cycle intermediates which can
be converted in
-glucose and glycogen
-can be oxidize for ATP energy
AMINO ACIDS
The liver also metabolizes amino acids that arrives intermittently from other tissues.
During a period between meals, especially if prolonged, some muscle proteins is degraded into
amino acids.
These amino acids donate their amino groups to
pyruvate, the product of glycolysis, ti yield alanine,
which is transported to the liver and deaminated.
The resulting pyruvate is converted by hepatocytes
into BLOOD GLUCOSE, and the ammonia is
converted into urea for excretion.
LIPIDS
Fatty acids are;
1.-converted into liver lipids.
2.-major oxidative fuel in the liver
Excess acetyl-CoA released on oxidation of
fatty acids is;
3.-converted into ketone bodies
Acetoacetate
b-hidroxybutyrate,
These are circulated in the blood to the other
tissues.
4.- used in the biosynthesis of cholesterol
5.- Fatty acids are converted to the
phospholipids and triacylglycerols of the plasma
lipoproteins, which carry to adipose tissue for
storage as triacylglycerols
6.- Some free fatty acids become bound to
serum albumin and are carried in the blood to
the heart and skeletal muscles.
ATP and GLYCOGEN
•The standard free energy of ATP is 7.3 Kcal/mole or 30.5 Kj/mole
•Under most conditions, the liver obtains its ATP
-In the largest fraction of through the oxidation of fatty acids
-In less fraction from the oxidation of pyruvate formed in glycolysis
from lactate brought from skeletal muscle and blood cells
•Glycogen stored in the liver is used primarily to provide glucose to the blood for
distribution to tissues that require it for energy metabolism.
•However, some glucose 1-phosphate derived from glycogen is directed into the
glycolytic pathway yielding some ATP for use by the liver.
•The cost in energy for the storage of glucosyl units into glycogen is modest relative
to the functions served.
•Casting of glucose into its polymeric form allows a relative large amount to be stored
in hepatocytes without
-Lost by diffusion
-The osmotic consequences of store a monosacaride.
Muscle uses ATP for mechanical work
•Metabolism in skeletal muscle is specialized to generate ATP as the immediate source of energy.
•In resting muscle, the primary fuels are free fatty acids from adipose tissue and ketone
bodies from the liver. Acetyl-CoA
ATP
In Muscle
Muscle uses ATP for mechanical work
•Moderately active muscles uses blood glucose in addition to fatty acids and ketone bodies.
Blood
Glucose
In Muscle
Piruvate
Muscle uses ATP for mechanical work
•In maximal active muscles, the demand for ATP is so great
that the blood flow cannot provide O2 and fuels fast enough to
produce the necessary ATP by aerobic respiration alone. Under
these conditions, stored muscle glycogen is broken down to
lactate by fermentation.
•Lactic acid fermentation thus provides extra ATP energy
quickly
Muscle uses ATP for mechanical work
•The use of blood glucose and muscle glycogen as fuels for muscular activity is greatly
enhanced by the secretion of epinephrine, which stimulates the formation of blood glucose from
glycogen in the liver and the breakdown of glycogen in muscle tissue.
•Skeletal muscle does not contain glucose-6-phosphatase and can not convert glucose-6phosphate to free glucose for export to other tissues.
•Consequently, muscle glycogen is completely dedicated to providing energy in the muscle, via
glycolysis.
Muscle
ATP
Pyruvate
Ephinephrine
Glycogen
Glucose-6-phosphate
Liver
Free Glucose
Export to other tissues
Glycolysis
Glucose
Glucose-6-phosphatase Liver enzime
Glucose-6-P
Fructose-6-P
Glyceraldehyde 3-P
Fructose-1,6-bisP
1,3-Bisphosphoglycerate
Dihydroxyacetone phosphate
3- phosphoglycerate
2- phosphoglycerate
phosphoenolpyruvate
pyruvate
Muscle uses ATP for mechanical work
•The minute-by-minute adjustment that keep the blood glucose level near 4.5 mM involve
the combined actions of insulin, glucagon and epinephrine, especially in liver, muscle and
adipose tissue.
Insulin signals these tissues that
the blood glucose concentration is
higher than necessary.
Glucagon carries the message
that blood glucose is too low.
Epinephrine is released into the
blood to prepare the muscles,
lungs and heart for a burst of
activity.
Muscle uses ATP for mechanical work
Muscle uses ATP for mechanical work
GLUT 2
•Hepatocyte membranes are equipped with hexose transporters that facilitate
the movement of the sugars into and out of the cells.
•The main transporter of glucose in the hepatocyte is called GLUT 2.
•Its expression is limited to sinusoidal membranes, and is not present in apical
and bile canalicular membranes.
•GLUT 2 of hepatocytes is not translocated to intracellular membranous
vesicles, but remains associated with the plasma membranes.
•GLUT 2 is insensible to insulin
•The transporter in hepatocytes is symmetrical, the Km values for glucose entry
and glucose exit are both about 20 mM.
GLUT 2
•Thus the movement of glucose into and out of hepatocytes is controlled by
hormonal regulation of enzymes involved in glycolysis, glycogen synthesis,
and gluconeogenesis, and not by hormonal regulation of the glucose
transporter (GLUT 2) per se.
OUT
Hormones
IN
-
GLUT 2
[GLUCOSE]
+
[GLUCOSE]
GLUT 2
GLUT 2
[GLUCOSE]
OUT
+
Hormones
[GLUCOSE]
GLUT 2
IN
GLUT 2
•GLUT 2 occurs in isolated hepatocytes, basolateral membranes of intestinal
cells, and in pancreatic islet cells.
•GLUT 2 has been reported to be up-regulated by glucose and counteracted
by insulin.
•In diabetic rats after sequential transient hypoglycemia followed
hyperglycemia, the GLUT 2 mRNA and protein expression is up-regulated
by
•GLUT 2 is more highly expressed in the periportal cells of the liver, also a
characteristic of the gluconeogenic enzymes.
•This type of regulation would support the argument that up-regulation of GLUT
2 was more critical in glucose export from the liver to maintain glucose
homeostasis than in import.
•During times when the liver is importing glucose, basal levels of GLUT 2
expression are sufficient to support oxidation.
•Glucose transport out of the lumen of the ER is also required to have a net
glucose output