Dsb 106. intergration of metabolism.2014
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Transcript of Dsb 106. intergration of metabolism.2014
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DSB 106: Digestive system and Metabolism
Lecture TitleMetabolic Integration
Lecturer: Dr. G. Kattam Maiyoh,
Department of Medical Biochemistry, SOM
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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
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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.
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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 !!!
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Key Junctions between Pathways
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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)
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Figure 27.7 Metabolic relationships among the major human organs.
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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
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Metabolic Profile of Organs
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Brain
Brain has two remarkable metabolic features1. Very high respiratory metabolism
20 % of oxygen consumed is used by the brain
2. 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
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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
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The Brain Will Make Ketone Bodies If It’s Starving for Glucose
Acetyl-CoA
GKM/DSB106/DIG.SYS.MET/2013
1. Acetoacetate2. β-hydroxy-butyrate3. Acetone
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Figure 27.8 Ketone bodies such as β-hydroxybutyrate provide the brain with a source of acetyl-CoA when glucose is unavailable.
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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
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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
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Creatine Kinase and Phosphocreatine Provide an Energy Reserve in Muscle
Figure 27.9 Phosphocreatine serves as a reservoir of ATP-synthesizing potential.
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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
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Figure 27.10 The transamination of pyruvate to alanine by glutamate:alanine aminotransferase.
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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) GKM/DSB106/DIG.SYS.MET/2013
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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
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Heart and metabolic profile
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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
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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
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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
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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
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• 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
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Figure 27.11: Metabolic conversions of glucose-6-phosphate in the liver.
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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
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Metabolic Activities of the Liver (Amino Acids)
α-Ketoacids (derived from amino acid degradation) -> liver’s own fuel
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Metabolic Activities of the Liver (Fatty Acids)
cannot use acetoacetate as fuel
-> almost no transferase to generate acetyl-CoA
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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)
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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!
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Blood-Glucose
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Postabsorptive stateGlucose + 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
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Insulin Secretion –Stimulated by Glucose Uptake
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Postabsorptive State -> after a Meal
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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
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Early Fasting State -> During the Night
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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
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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
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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
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Mobilization at Starvation
Also at not treated diabetes
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Diabetes Mellitus – Insulin InsufficiencyCharacterized 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
GKM/DSB106/DIG.SYS.MET/2013
Dehydration results following the osmotic movement of water into urine
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• 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)GKM/DSB106/DIG.SYS.MET/2013
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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
GKM/DSB106/DIG.SYS.MET/2013
Leptin controls what we eat and how much we eat and how we feel after a meal.
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GKM/DSB106/DIG.SYS.MET/2013
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The Role of Leptin and Insulin on Weight Control
Leptin is a hormone that is produced in direct proportion to fat mass (adipocytes)
GKM/DSB106/DIG.SYS.MET/2013
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High Levels of Leptin and Insulin are a Signal for “caloric homeostasis”
GKM/DSB106/DIG.SYS.MET/2013
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Obese People Produce More Heat
Body can deal with excess calories:
1. Storage
2. Extra exercise
3. Production of heatGKM/DSB106/DIG.SYS.MET/2013
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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)
GKM/DSB106/DIG.SYS.MET/2013
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Ethanol Alters Energy Metabolism in LiverConsumption 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
GKM/DSB106/DIG.SYS.MET/2013
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• 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)
GKM/DSB106/DIG.SYS.MET/2013
More damaging effects of alcohol!
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THE END
THANKS FOR YOUR ATTENTION