Download Brain Needs in Different Metabolic states

Brain Needs in Different Metabolic states
Learning Objectives
At the end of the lecture, the students should be able to
• Describe the stats of the brain.
• Explain the mechanism and mode of metabolism in a post aborptive
state.
• Discuss the mechanism and mode of metabolism in a post aborptive
state.
• Describe the brain in postabsorptive and fasting states.
• Explain the removal of ammonia and glutamate from the brain.
Definition…
• Metabolism – the sum of all the chemical processes
whereby _______ is made available and used by the cells
of the body
• Energy– the ability to do work
Energy is used for…
• Adult human require 10 – 12 MJ (2400 – 2900 Kcal) (1
kcal = 4.18 Joule ) from metabolic fuel each day.
• 40 -60 % from carbohydrate
• 30 -40 % lipids
• 10 – 15 % proteins.
• In starving state glucose spared for use by the central
nervous system and erythrocytes.
ENERGY METABOLISM AT THE ORGAN LEVEL
• Although the brain represents only 2% of the body weight:
• It receives 15% of the cardiac output,
• 20% of total body oxygen consumption. The brain is extremely
sensitive to hypoxia, and occlusion of its blood supply produces
unconsciousness in as short a period as 10 seconds.
• 25% of total body glucose utilization.
• The brain’s consumption of glucose and oxygen are constant
regardless of resting/ sleeping or active/ waking
Major features of metabolism of the principal organ
• Liver: Service for the other organs and tissues
major pathways: gluconeogensis, beta oxidation, ketogensis, urea,
uric and bile formation, cholesterol synthesis.
• Brain: coordination of nervous system
Major pathways: Glycolysis, amino acid metabolism
• Adipose tissues: Storage and breakdown of TG
Esterification of fatty acids and lipolysis, lipogensis
• Muscle:
• Erythrocytes:
• Kidney
:
Brain Metabolism
• High energy requirements (~1.0 mg/kg/min)
• Low energy reserves
•
The energy is needed to maintain the ionic gradient across
nerve membranes.
• The glucose transporter, GLUT-1, is enriched in the brain capillary
endothelial cells and mediates the facilitated diffusion of glucose
through the blood brain barrier.
• Most of the glucose is metabolized to pyruvate, which enters the
mitochondria of neurons and glia and is converted to acetyl-CoA
before entering the TCA cycle.
• Only about 13% of glycolytic pyruvate is converted to lactate under
normal condition.
Name
GLUT1
GLUT2
[edit] Classes II/III
Distribution
Notes
Is widely distributed in fetal tissues. In the adult, it is expressed
at highest levels in erythrocytes and also in the endothelial cells Levels in cell membranes are
of barrier tissues such as the blood –brain barrier. However, it is increased by reduced glucose
levels and decreased by increased
responsible for the low-level of basal glucose uptake
glucose levels.
required to sustain respiration in all cells.
Is expressed by renal tubular cells and small intestinal
epithelial cells that transport glucose, liver cells and
pancreatic beta cells. All three monosaccharides are .
transported from the intestinal mucosal cell into the portal
circulation by GLUT2
Is a high capacity and low
affinity isoform
GLUT3 Expressed mostly in neurons (where it is believed to be the main glucose
transporter isoform), and in the placenta.
Is a high-affinity isoform
GLUT4 Found in adipose tissues and striated muscle (skeletal muscle and cardiac
muscle.
Is the insulin-regulated glucose transporter. Responsible for insulin-regulated glucose
storage
1. Postabsorptive state
Glucose + Amino acids -> transport from intestine to blood
Dietary lipids transported -> lymphatic system -> blood
Glucose stimulates -> secretion of insulin
Insulin:
signals fed state
stimulates storage of fuels and synthesis of proteins
high level -> glucose enters muscle + adipose tissue (synthesis of TAG)
stimulates glycogen synthesis in muscle + liver
suppresses gluconeogenesis by the liver
accelerates glycolysis in liver -> increases synthesis of fatty acids->
accelerates uptake of blood glucose into liver -> glucose 6-phosphate more
rapidly formed than level of blood glucose rises -> built up of glycogen
stores
Insulin Secretion –Stimulated by Glucose Uptake
Postabsorptive State -> after a Meal
2. Early Fasting State
Blood-glucose level drops after several hours after the meal -> decrease
in insulin secretion -> rise in glucagon secretion
Low blood-glucose level -> stimulates glucagon secretion of α-cells of
the pancreas
Glucagon:
-> signals starved state
-> mobilizes glycogen stores (break down)
-> inhibits glycogen synthesis
-> main target organ is liver
-> inhibits fatty acid synthesis
-> stimulates gluconeogenesis in liver
-> large amount of glucose in liver released to blood stream -> maintain
blood-glucose level
Muscle + Liver use fatty acids as fuel when blood-glucose level drops
Early Fasting State -> During the Night
3. Refed State
 Fat is processed in same way as normal fed state
 First -> Liver does not absorb glucose from blood (diet)
 Liver still synthesizes glucose to refill liver’s glycogen stores
 When liver has refilled glycogen stores + blood-glucose level
still rises -> liver synthesizes fatty acids from excess glucose
Prolonged Starvation
Well-fed 70 kg human -> fuel reserves about 161,000 kcal
-> energy needed for a 24 h period -> 1600 kcal - 6000 kcal
-> sufficient reserves for starvation up to 1 – 3 months
-> however glucose reserves are exhausted in 1 day
Even under starvation -> blood-glucose level must be above 40 mg/100 ml
6
 F
atty acids are attached to lipoproteins and do not pass the
blood brain barrier as fuel substrates.
• The lactate is used for energy metabolism in adult brain, but this
remains somewhat controversial.
• While glucose is the preferred energy substrate, neurons and glia
will metabolize ketones for energy under fasting-induced reductions
of blood glucose.
Ketone bodies
•
•
•
•
Consisting of acetoacetate, and β -hydroxybutyrate (β-OHB)
Catabolism of fat in the liver
Concentration in blood is inversely related to that of glucose.
Ketone bodies are transported into the brain through the bloodbrain barrier monocarboxylic transporters (MCTs), whose
expression is regulated in part by circulating ketone and glucose
levels.
• β-OHB is the predominant
• Rapidly oxidized to acetyl-CoA in the mitochondria through an
enzymatic series involving 3-hydroxybutyrate dehydrogenase,
• SCOT (succinyl-CoA-acetoacetate-CoA transferase), and
mitochondrial acetyl-CoA thiolase
•
Acetone is a non-enzymatic byproduct of ketone body synthesis
and is largely excreted in the urine or exhaled from the lungs.
•
Ketone bodies are more energetically efficient than either pyruvate
or fatty acids because they are more reduced (greater
hydrogen/carbon ratio) than pyruvate and do not uncouple the
mitochondrial proton gradient as occurs with fatty acid metabolism.
In contrast to glucose, ketone bodies by-pass cytoplasmic
glycolysis and directly enter the mitochondria where they are
oxidized to acetyl-CoA
The amount of acetyl-CoA formed from ketone body metabolism is
greater than that formed from glucose metabolism.
ketone body metabolism can also reduce production of damaging
free radicals
•
•
•
Glycogen Metabolism
• Primarily stored in astrocytes
• Levels in brain are low compared to liver and muscle
• Turnover rate is very rapid; its synthesis and breakdown are
regulated by the two key enzymes glycogen phosphorylase and
synthase.
• Glycogen levels are tightly coupled to synaptic activity
• During anesthesia they rise sharply
• Regulated in Astrocytes by Norepinephrine and Vasoactive
Intestinal Peptide.
Glutamate Removal
• The brain's uptake of glutamate is approximately balanced by its
output of glutamine
• Glutamate entering the brain takes up ammonia and leaves as
glutamine
• The glutamate–glutamine conversion in the brain—the opposite of
the reaction in the kidney that produces some of the ammonia
entering the tubules—serves as a detoxifying mechanism to keep
the brain free of ammonia.
Ammonia Removal
• Ammonia is very toxic to nerve cells, and ammonia toxication is
believed to be a major cause of the bizarre neurologic symptoms in
hepatic coma.
• Ammonia may be toxic to the brain in part because it reacts with ketoglutarate to form glutamate. The resulting depleted levels of ketoglutarate then impair function of the tricarboxylic acid (TCA)
cycle in neurons.
All protein amino acids except lysine, theronine, proline participate
in transmanination.
• Transmamination intercoverts pairs of alpha amino acids and alpha
keto acids.
• Transfer of amino nitrogen to alpha ketoglutrate form L-glutmate,
By glutmate dehydrogenase ammonia produced.
• Glutamine + NH4 and glutaminase form glutamate.
Stroke
•
The blood supply to a part of the brain is interrupted,
•
There are two general types of strokes: hemorrhagic and ischemic.
•
Hemorrhagic stroke occurs when a cerebral artery or arteriole
ruptures.
•
Ischemic stroke occurs when flow in a vessel is compromised by
atherosclerotic plaques on which thrombi form.
•
It has now become clear ischemia reduces glutamate uptake by
astrocytes, and the increase in local glutamate causes excitotoxic
damage and death to neurons.
• In experimental animals and perhaps in humans, drugs that prevent
this excitotoxic damage significantly reduce the effects of strokes.
• In addition, clot-lysing drugs such as t-PA are of benefit.
• Both antiexcitotoxic treatment and (tissue plasmogen activator) t-PA
must be given early in the course of a stroke to be of maximum
benefit,
• it is important to determine if a stroke is thrombotic or hemorrhagic,
since clot lysis is contraindicated in the latter.
References
• Harpers Biochemistry
• Lippincott Review of biochemistry
• Medical Biochemistry by Chatterji
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