Dsb 106. intergration of metabolism.2014

DSB 106: Digestive system
and Metabolism
Lecture Title
Metabolic Integration
Lecturer:
Dr. G. Kattam Maiyoh,
Department of Medical Biochemistry,
SOM

Integration of Metabolism
1. Interconnection of
pathways
2. Metabolic profile of organs
3. Food intake, starvation
and obesity
4. Fuel choice during
exercise
5. Ethanol alters energy
metabolism
6. Hormonal regulation of
metabolism

Integration
• The human body functions as one community.
• Communication between tissues is mediated by the
nervous system, by the availability of circulating
substrates and by variation in the levels of plasma
hormones.
• The integration of energy metabolism is controlled
primarily by the action of hormones, including
insulin, glucagon and catecholamines (epinephrine
and nor epinephrine).
• The four major organs important in fuel metabolism
are liver, adipose tissue muscle and brain.

6
Connection of Pathways
1. ATP is the universal currency of
energy
2. ATP is generated by oxidation of
glucose, fatty acids, and amino
acids ; common intermediate ->
acetyl CoA ; electron carrier ->
NADH and FADH2
3. NADPH is major electron donor in
reductive biosynthesis
4. Biomolecules are constructed from
a small set of building blocks
5. Synthesis and degradation
pathways almost always separated
-> Compartmentation !!!

7
Key Junctions
between Pathways

How Is Metabolism Integrated in a
Multicellular Organism?
• Organ systems in complex multicellular organisms
have arisen to carry out specific physiological
functions
• Such specialization depends on coordination of
metabolic responsibilities among organs so that the
organism as a whole can thrive
• Organs differ in the metabolic fuels they prefer as
substrates for energy production (see Figure 27.7)

Figure 27.7 Metabolic
relationships among the major
human organs.

How Is Metabolism Integrated in a
Multicellular Organism?
• The major fuel depots in animals are glycogen in
liver and muscle; triacylglycerols in adipose tissue;
and protein, mostly in skeletal muscle
• The usual order of preference for use of these is
glycogen > triacylglycerol > protein
• The tissues of the body work together to maintain
energy homeostasis

12
Metabolic Profile of Organs

Brain
Brain has two remarkable metabolic features
1. Very high respiratory metabolism
20 % of oxygen consumed is used by the brain
1. But no fuel reserves (ooopps!)
Uses (mostly) glucose as a fuel and is dependent on the blood for a
continuous incoming supply (120g per day)
In fasting conditions, brain can use ketone bodies,
converting them to acetyl-CoA for the energy
production via TCA cycle
Goal: Generate ATP to maintain the membrane
potentials essential for transmission of nerve
impulses

14
Metabolic Profile of Brain
Glucose is fuel for human brain -> consumes 120g/day -> 60-70 % of
utilization of glucose in starvation -> ketone bodies can replace
glucose

The Brain Will Make Ketone Bodies If It’s Starving for Glucose
Acetyl-CoA
GKM/DSB106/DIG.SYS.MET/2013
1. Acetoacetate
2. β-hydroxy-butyrate
3. Acetone

Figure 27.8
Ketone bodies
such as β-
hydroxybutyrate
provide the brain
with a source of
acetyl-CoA when
glucose is
unavailable.

Muscle
• Skeletal muscles is responsible for about 30%
of the O2 consumed by the human body at rest
• Muscle contraction occurs when a motor nerve
impulse causes Ca2+
release from
endomembrane compartments
• Muscle can utilize a variety of fuels --glucose,
fatty acids, and ketone bodies
• Resting muscle contains about 2% glycogen
and 0.08% phoshpocreatine

Creatine Kinase in Muscle
• For about 4 seconds of exertion, phosphocreatine
provide enough ATP for contraction
• During strenuous exertion, once phosphocreatine is
depleted, muscle relies solely on its glycogen
reserves
• Glycolysis is capable of explosive bursts of activity,
and the flux of glucose-6-P through glycolysis
can increase 2000-fold almost
instantaneously
• However, glycolysis rapidly lowers pH (lactate
accumulation), causing muscle fatigue

Creatine Kinase and Phosphocreatine
Provide an Energy Reserve in Muscle
Figure 27.9 Phosphocreatine
serves as a reservoir of ATP-
synthesizing potential.

Muscle Protein Degradation
• During fasting or excessive activity, (in
muscle) amino acids are degraded to pyruvate,
which can be transaminated to alanine
• Alanine circulates to liver, where it is
converted back to pyruvate – a substrate for
gluconeogenesis
• This is a fuel of last resort for the fasting or
exhausted organism

Figure 27.10 The transamination of pyruvate to alanine by glutamate:alanine
aminotransferase.

2. Metabolic Profile of Muscles
Major fuels are glucose, fatty acids, and ketone bodies
-> has a large storage of glycogen -> about ¾ of all
glycogen stored in muscles
-> glucose is preferred fuel for burst of activity ->
production of lactate (anaerobic)
-> fatty acid major fuel in resting muscles and in heart
muscle (aerobic)

Heart
• The activity of heart muscle is constant and
rhythmic
• The heart functions as a completely aerobic
organ and is very rich in mitochondria
• Prefers fatty acid as fuel
• Continually nourished with oxygen and free
fatty acid, glucose, or ketone bodies as fuel

Adipose tissue (Energy Storage Depot)
• Amorphous tissue widely distributed about the body
• Consist of adipocytes
• ~65% of the weight of adipose tissue is
triacylglycerol
• There is a continuous synthesis and breakdown of
triacylglycerols, with breakdown controlled largely
via the activation of hormone-sensitive lipase
• Adipose lack glycerol kinase; cannot recycle the
glycerol of TAG

26
Metabolic Profile of Adipose tissue
Triacylglycerols are
stored in tissue ->
enormous reservoir of
metabolic fuel
-> needs glucose to
synthesis TAG;
-> glucose level
determines if fatty acids
are released into blood

Brown fat
• A specialized type of adipose tissue, is
found in newborn and hibernating animals
• Rich in mitochondria
• Also with thermogenin, uncoupling protein-
1, permitting the H+
ions to re-enter the
mitochondria matrix without generating
ATP
• Is specialized to oxidize fatty acids for heat
production rather than ATP synthesis

Liver (NUTRIENT DISTRIBUTION CENTER )
• The major metabolic processing center in
vertebrates, except for triacylglycerol
• Most of the incoming nutrients that pass
through the intestines are routed via the portal
vein to the liver for processing and distribution
• Liver activity centers around glucose-6-
phosphate

• Glucose-6-phosphate
– From dietary carbohydrate, degradation of glycogen, or
muscle lactate
– Converted to glycogen
– released as blood glucose,
– used to generate NADPH and pentoses via the pentose
phosphate pathway,
– catabolized to acetyl-CoA for fatty acid synthesis or for
energy production in oxidative phosphorylation
• Fatty acid turnover
• Cholesterol synthesis
• Detoxification organ
Key liver metabolic assignments

Figure 27.11: Metabolic conversions
of glucose-6-phosphate in the liver.

31
Metabolic Profile of the
Liver (Glucose)
Essential for providing
fuel to brain, muscle,
other organs
-> most compounds
absorbed by diet
-> pass through liver ->
regulates metabolites in
blood

32
Metabolic Activities of the Liver (Amino Acids)
α-Ketoacids (derived
from amino acid
degradation)
-> liver’s own fuel

33
Metabolic Activities of the Liver (Fatty Acids)
cannot use
acetoacetate as
fuel
-> almost no
transferase to
generate acetyl-
CoA

Metabolic Profile of Kidney
Production of urine -> secretion of waste products
Blood plasma is filtered (60 X per day) -> water and
glucose reabsorbed
-> during starvation -> important site of
gluconeogenesis (1/2 of blood glucose)

35
Food Intake, Starvation, and Obesity
Normal Starved-Fed Cycle:
1. Postabsorptive state -> after a meal
2. Early fasting state -> during the night
3. Refed state -> after breakfast
-> Major goal is to maintain blood-glucose level!

37
Postabsorptive state
Glucose + Amino acids -> transport from intestine to blood
Dietary lipids transported -> lymphatic system -> blood
Glucose stimulates -> secretion of insulin (others – amino acids and
intestinal hormones e.g. secretin)
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

38
Insulin Secretion –Stimulated by Glucose Uptake

39
Postabsorptive State -> after a Meal

40
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

41
Early Fasting State -> During the Night

42
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

43
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

44
First priority -> provide sufficient glucose to brain and other tissues that are
dependent on it
Second priority -> preserve protein -> shift from utilization of glucose to utilization of
fatty acids + ketone bodies
-> mobilization of TAG in adipose tissues + gluconeogenesis by liver -> muscle shift
from glucose to fatty acids as fuel
After 3 days of starvation -> liver forms large amounts of ketone bodies (shortage of
oxaloacetate) -> released into blood -> brain and heart start to use ketone bodies as
fuel
After several weeks of starvation -> ketone bodies major fuel of brain
After depletion of TAG stores -> proteins degradation accelerates -> death due to loss
of heart, liver, and kidney function
Prolonged Starvation

46
Mobilization at Starvation
Also at not
treated
diabetes

Diabetes Mellitus – Insulin Insufficiency
Characterized by: -> high blood-glucose level
-> Glucose overproduced by liver
-> glucose underutilized by other organs
Results in a shift in fuel usage from carbohydrates
to fats
Leads to production of ketone bodies (shortage of
oxaloacetate)
-> high level of ketone bodies ->ketosis - kidney
cannot balance pH any more -> lowered pH in blood
and dehydration -> coma
Dehydration results following the osmotic movement of water into urine

• Type I diabetes: insulin-dependent diabetes (requires insulin to live)
• caused by autoimmune destruction of β-cells
• begins before age 20 (early onset)
• -> insulin absent -> glycagon present
• -> entry of glucose into cells is blocked
– -> person in biochemical starvation mode + high blood-glucose level
• -> glucose excreted into urine -> also water excreted -> feel hungry
+ thirsty
• Type II diabetes: insulin-independent diabetes
• have a normal-high level of insulin in blood -> body cells are
unresponsive to hormone (insulin)
• develops in middle-aged, obese people (late on-set)

Obesity
In the U. S. -> about 70% of adults are suffering from obesity (2009),
Kenya is on the rise.
Risk factor for: Diabetes + Cardiovascular diseases
Cause of Obesity -> more food consumed than needed -> storage of
energy as fat
There are two important signals for “caloric homeostasis” and “appetite”
control -> insulin + leptin
Mouse lacking
leptin
or Leptin
receptor
Leptin controls what we eat
and how much we eat and
how we feel after a meal.

The Role of Leptin and Insulin on Weight
Control
Leptin is a
hormone that
is produced in
direct
proportion to
fat mass
(adipocytes)

High Levels of Leptin and Insulin are a
Signal for “caloric homeostasis”

Obese People
Produce More Heat
Body can deal with excess calories:
1. Storage
2. Extra exercise
3. Production of heat

Fuel Choice During Exercise
Fuels used are different in:
-> sprinting -> anaerobic exercise -> lactate
-> distance running -> aerobic exercise -> CO2
Sprint: powered by ATP, creatine phosphate, and anaerobic
glycolysis of glucose -> lactate
Medium length sprint: complete oxidation of muscle glycogen -> CO2
(production slower) -> velocity lower
Marathon: complete oxidation of muscle and liver glycogen -> CO2
and complete oxidation of fatty acids from adipose tissues -> CO2
(ATP is generated even slower)

Ethanol Alters Energy Metabolism in Liver
Consumption of EtOH in excess leads to anumber of health problems
EtOH has to be metabolised:
1. EtOH + NAD+
-> Acetaldehyde + NADH (alcohol dehydrogenase,
in cytoplasm)
2. Acetaldehyde + NAD+
-> Acetate + NADH (aldehyde dehydrogenase,
in mitochondria)
-> EtOH consumption leads to accumulation of NADH
High level NADH causes:
-> inhibition of gluconeogenesis (prevent oxidation of lactate to pyruvate) ->
lactate accumulates
-> inhibits fatty acid oxidation -> stimulates fatty acid synthesis in liver -> TG
accumulates -> fatty liver
-> inhibition of citric acid cycle

• Ethanol inducible microsomal ethanol-oxidizing system (MEOS) ->
P450 dependent pathway -> generates free oxygen radicals ->
damages tissues
• Acetate is converted into Acetyl CoA -> processing of Acetyl
CoA by citric acid cycle is blocked by high amounts of NADH ->
Ketone bodies are generated and released into the blood ->
further drop of pH
• Processing of acetate in liver inefficient resulting in high level of
acetaldehyde in liver -> reacts with proteins -> become inactive ->
damage liver -> cell death
• Alcohol induced Liver damage occurs in 3 stages: Development of
Fatty Liver -> alcoholic hepatitis (groups of cells die) -> cirrhosis
(no convertion of Ammonium -> urea)
More damaging effects of alcohol!

THE END
THANKS FOR YOUR
ATTENTION

Dsb 106. intergration of metabolism.2014

Recommandé

Recommandé

Contenu connexe

Tendances

Tendances (20)

En vedette

En vedette (6)

Similaire à Dsb 106. intergration of metabolism.2014

Similaire à Dsb 106. intergration of metabolism.2014 (20)

Plus de Dr. Geoffrey K. K. Maiyoh

Plus de Dr. Geoffrey K. K. Maiyoh (20)

Dernier

Dernier (20)

Dsb 106. intergration of metabolism.2014