intermediary metabolism - univerzita karlovavyuka-data.lf3.cuni.cz/cvse1m0001/intermediary...
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Metabolic roles of tissues • Four major tissues play a dominant role in fuel
metabolism : liver, adipose, muscle, and brain.
• These tissues do not function in isolation.
• Communication between tissues is mediated by the nervous systém, by the availability of circulating substrates, and by variation in the levels of plasma hormones.
• The integration of energy metabolism is controlled by the actions of two peptide hormones, insulin, and glucagon (response to changing substrate levels) with catecholamines epinephrine and norepinephrine (response to neural signals).
Liver lies immediately under the diaphragm. It is supplied
with blood from below through two major vessels: the
hepatic artery (20% of blood) and the hepatic portal vein
which brings the substrates (soluble in water) absorbed
from the intestinal tract including stomach into the blood
and then directly to liver.
Pancreatic vein (insulin, glucagon)
Liver consumes 20 – 30% of total oxygen consumption
Functions of the liver The uptake of nutrients delivered from the
digestive tract via portal vein
The synthesis, storage, interconversion and
degradation of metabolite
The regulated supply of energy-rich
The detoxification of harmful compounds by
The excretion of substances with the bile;
synthesis and degradation of many blood plasma
Carbohydrate metabolism in the liver- fed
Concentration in portal vein after a meal up to 10 mmol/l – GLUT-2 –
type glucose transporter not responsive to insulin, relatively high Km
(rate and direction of movement of glucose through hepatocyte
membrane are determined by concentration inside and outside the cell)
Glucokinase (Km= 12 mmol/l) x hexokinase 0.1 mmol/L
Any increase in glucose concentration against blood conc. leads to
proportional increase in the rate of phosphorylation by glucokinase
.Likewise any decrease in glucose conc. leads to proportional decrease
in the rate of phosphorylation.
Thus liver uses glucose at significant rate only when blood glucose level
is greatly elevated.
The overall result is that when glucose conc. outside the hepatocyte
rises, glucose will be rapidly taken into cells and phosphorylated.
Carbohydrate metabolism in the liver-
The presence of high-Km glucose transporter and
high-Km glucokinase do not enable the hepatocyte
to take up unlimited quantities of glucose as G-6-P
There are specific mechanisms for stimulating the
disposal of Glu-6-P
Glycogen synthesis (activation of glycogen
synthase by insulin and glucose)
Glycolysis metabolizes glucose to pyruvate
TCA, some released after conversion to lactate.
But minor energy source for liver.
Metabolic Fate of G6P
Carbohydrate metabolism –
overnight fasted conditions
Glycogen breakdown (glycogenolysis), controlled by
reciprocal activation of glycogen phosphorylase by
glucagon, adrenalin, noradrenalin, catecholamines.
Glu-1-P produced by glycogenolysis is in equilibrium
with Glu-6-P (enzyme phosphoglucomutase).
Formation of glucose from Glu-6-P is produced by
enzyme Glu-6-phosphatase (membrane ER)
Carbohydrate metabolism in the liver
Synthesis of glucose – gluconeogenesis
Substrates : lactate, alanine, glycerol
Hepatic gluconeogenesis can be also stimulated by
increase in the supply of substrate from other tissue
(after physical exercise-lactate, starvation-glycerol)
and by hormones (glucagon)
Glucose paradox (gluconeogenesis after meal)
The pentose phosphate pathway – alternative fate for
Glu-6-P, conversion to five-carbons sugars (ribose-5-
P for synthesis of nucleic acids)
Formation of NADPH for reductive synthesis
Fat metabolism in the liver
The metabolism of lipids in the liver is closely
linked to metabolism of carbohydrates and
The pathwayof FA oxidation diverges from that
of glycerolipid synthesis when acyl-CoA enters
the mitochondrion for oxidation.
Carnitine-palmitoyl transferase-1 (CPT-1).
Activity of this enzyme is strictly regulated by
means of compound malonyl-CoA (potent
inhibitor). This role of malonyl-CoA provides a
vital link between carbohydrate and fat
Fat metabolism in the liver
The liver converts glucose (Glc) via Acetyl-CoA into
fatty acids (FA) - cytosol. FA and chylomicrons are
used as a sources – neutral fats and phospholipides. In
humans FA synthesis from other molecules (Glc) is
usually small in comparison with dietary fatty acid
VLDL are formed in smooth ER of hepatocytes.
High concentration of acetyl-CoA (postabsorptive
state, starvation) as a result of β-oxidation of FA in
mitochondrion great amount of ketone bodies :
acetoacetate, 3-hydroxybutyrate and acetone.
Fat metabolism in the liver
Cholesterol has two sources, the diet and de
novo synthesis (in liver significant amount).
Some cholesterol is required for synthesis of bile
acids, some for cell membranes, some is stored
in the form of lipids droplets in esterified form.
The rest in free and esterified form in VLDL (to
supply another tissues)
The liver also degrades lipoprotein complexes
(with cholesterol and cholesterol esters) taking
up from the blood.
Amino acid metabolism in the liver
Our bodies do not continuously accumulate or
lose protein in a net sense. The rate of AA
oxidation in the body must therefore balance the
rate of entry of dietary protein (70-100g per day)
Catabolism of AA occurs predominantly in the
liver with exceptions (branched chain amino
acids in muscles)
AA oxidation provides ½ of the liver´s energy
It is also the only organ capable of eliminating
the nitrogen from amino acids by urea cycle
• The starve-feed cycle allows a variable fuel and nitrogen consumption to meet a variable metabolic and anabolic demand. Feed refers to intake of meals (variable fuel) after which we store the fuel in the form of glycogen and fat, to meet our metabolic demand while we fast. ATP is energy-transferring agent in this cycle.
Well-Fed State – Amino acids Dietary proteins are hydrolyzed in the intestine (some
of them are used like energy source here : Asp, Asn, Glu, Gln→Ala, Lac, citrul, Pro into the portal blood)
Liver lets most of AA coming from intestine pass through, for synthesis of proteins in peripheral tissue , thanks to high Km .High Km allows to AA to be in excess without catabolism.
Utilization of AA for proteosynthesis (much lower
Km for tRNA-charging enzymes)
Excess of AA can be oxidized to CO2 , water, urea, or metabolites can be used as substrates for lipogenesis
Well-Fed State - glucose
Glucose → glycogen (glycogenesis), pyruvate, lactate
(glycolysis), for pentose phosphate pathway
Much of glucose from intestine passes through liver
to reach other organs (brain, testis, RBC, renal
Number of tissues produce lactate and pyruvate from
circulating glucose, which are taken up by liver , and
fat is formed lipogenesis)
In well-fed state liver does not engage in
Cori cycle is interrupted
Well-βFed State – fat
Glucose, lactate, pyruvate and AA support hepatic lipogenesis.
Fat formed from these substrates is released in the form of VLDL
Chylomicrons, VLDLs circulate in the blood until they meet lipoprotein lipase (near AT), hydrolysis of TAG (FA taken up adipocytes, reesterified with glycerol-3-phosphate to form TAG)
During well-fed state insulin from cells of the pancreas is in high concentration. These cells are very responsive to the influx of glucose and AA in the fed state.
Rate of insulin/glucagon
Early fasting state
Lipogenesis is curtailed
Lactate, pyruvate and AA are diverted into formation
glucose completing Cori cycle (conversion glucose to
lactate, pyruvate in peripheral tissue, they are
substrates for gluconeogenesis in liver)
Alanine cycle, in which carbon and nitrogen retu