Metabolic integration Flashcards
what is metabolic integration
- interconnection of pathways
- allows tissue differences
- communication between tissues (hormones, metabolites)
- inter-regulation of pathway (not always active)
key metabolic pathways
- glucose oxidation
- gluconeogenesis
- fatty acid synthesis
- beta oxidation of FA
- gluconeogenesis from pyruvate
- these are all independent and separate
- they have different metabolic outcomes
- they occur in different environmental circumstances
example of tissue specific enzyme expression: ketone metabolism
KETONE BODY METABOLISM
Liver: formation of ketone body
HMG-CoA -> acetoacetate + acetly Co-A
ENZYME: HMG-CoA lyase is liver specific
Extrahepatic tissues: ketone bod oxidation
Acetoacetate + Succinyl-CoA -> Acetoacetyl CoA + succinate
ENZYME: beta-ketoacyl-CoA transferase is only expressed in non-liver cells
= Ketone bodies are synthesised in liver but metabolised outside of the liver becuase of the expression of enzymes
most common ketone bodies
- acetoacetate
- beta-hydroxybutyrate
- acetone
what is ketogenesis
formation of ketone bodies from fatty acids and amino acids
process of ketogenesis
- in the liver, 2 acetyl CoA combine to form acetoacetate CoA
- acetoacetate combines with acetyl coA to form HMG-CoA
- HMG-CoA is degreaded in the mitochondria to form acetoacetate and acetyl CoA by action of HMG-CoA lyase
- acetoacetate can be reduced to beta-hydroxybutyrate and they both enter the blood
what can spontaneously happen to acetoacetate
- break down to CO2 and acetone
- acetone CANNOT be converted back to acetyl CoA§
ketone oxidation
- extrahepatic tissues convert acetoacetate and beta-hydroxybutyrate back to acetyl-CoA
beta-hydroxybutyrate -> acetoacetate
enzyme: beta-hydroxy dehydrogenase
Acetoacetate + Succinyl-CoA -> Acetoacetyl CoA + succinate
enzyme: betaketoacyl-CoA transferase
acetoacetyl CoA -> 2 acetyl CoA
enzyme: beta-ketothiolase
example of tissue specific enzyme expression: glycogen metabolism
liver: G6P -> Glucose
enzyme: glucose 6 phosphatase, in the liver only
muscle: G6P -> F6P -> Glycolysis & krebs
enyme: phosphoglucoisomerase
= in the liver glycogen is broken down to produce blood glucose where as in the muscle glucose cannot be directly produced, and instead F6P enters glycolysis and TCA to produce ATP
examples of glycogen storage diseases
- Van Gierke’s disease
- McArdles desease
Van Gierke’s disease
glycogen storage disease
- deficiency of liver G6P
- fasting hypoglycaemia
- unable to use liver glycogen to maintain glucose level
McArdles disease
glycogen storage disease
- deficiency of muscle glycogen phosphorylase
- unable to do prolonged exercise
- unable to use muscle glycogen for energy
where does glycolysis occur
liver, muscle, adipose, brain, RBC
where does kreb cycle occur
liver, muscle, adipose, brain
where does beta oxidation of FA occur
liver, muscle, adipose
where does glycogen breakdown occur
liver and muscle
where does ketone body oxidation occur
muscle and brain, conditionally
where organ is considered the metabolic heart
liver
where do all the main anabolic processes occur
liver
differential regualtion
happen at different times
differential regulation of glycogen metabolism
- glucagon stimulates phosphorylase = glycogen breakdown
- glucagon inhibits glycogen synthase
it would be a waste of energyo make and break glycogen at the same time. they occur differenetially
differential regulation of fatty acid metabolism
FA oxidation and FA synthesis do not occur at the same time
- malonyl CoA inhibits cartinine transport of fatty acyl-CoA
= the first committes steps for FA synthesis inhibts the first steps of FA oxidation
how do tissues communicate
- metabolites in the blood
- hormones in the blood
- nervous signals from CNS
examples of blood metabolites for tissue communication
glucose
lactate
FA
ketone bodies
examples of hormones in the blood for tissue communication
insulin
glucagon
adrenaline
cortisol
examples of nervous signel from CNA for tissue communication
noradrenalne
Cori cycle
muscle produces lactate anerobic glyocolysis -> travels in blood to the liver -> liver converts to glucose -> travels in blood to muscle REPEAT
similar process occur in RBC
what is insulin produced in response to
high glucose
what is glucagon produced in response to
low glucose
hormonal control od metabolism reguated by
glucagon and insulin
levels of blood glucose, insulin and glucagon in the fasted state
low blood glucose
low insulin
high glucagon
levels of blood glucose, insulin and glucagon in the fed state
high blood glucose
high insulin
low glucagon
what processes increase and decrease in the liver in the fasted state
increased: gluconeogenesis, beta oxidation,
decreased: glycogen synthesis, FA synthesis, glycogenolysis
what happens in the muscle in fasted state
reduced glycogen synthesis
what happens in the adipose in fasted state
increases release of FA
decreases FA synthesis
decreased TAG synthesis, time dependent (not initially)
what processes increase and decrease in the liver in the fed state
increased: glycogen synthesis, beta oxidation, FA synthsis
decreased: gluconeogenesis, glycogenolysis
what happens in the muscle in fed state
increased glucose uptake and glycogen synthesis
decreased glycogen breakdown
what happens in the adipose in fed state
increased FA synthesis and glucose uptake
decrease FA release
xenobiotics
synthetics, not found in human cells
effect of xenobiotics on human metabolism
- body is well adapted to metabolise a range of normal food stuffs
- drugs that inhibits one pathwayy can have effects on other parts of body’s system
some substances are better metabolised that others
e.g ethanol is not a normal part of the diet but body is able to effectively metabolise it
ethanol metabolism
- ethanol -> acetaldehyde
enzyme: alcohol dehydrogenase, NAD+ -> NADH + H+ - acetaldehyde -> acetate
enzyme: aldehyde dehydrogenase, NAD+ -> NADH +H+
What does ethanol metabolism require
NAD+ as cofactor, which produced NADH and has consequences
acetaldehyde
ethanAl
pyruvate/lactate equilibrium
NADH + H+ ——-> NAD+
pyruvate lactate
NADH + H+ < ——- NAD+
enzyme: lactate dehydrogenase
increased NADH:NAD+ resutls in increased lactate:pyruvate
why is lactate a dead-end molecule
only goes back to pyruvate, does nothing else
how does ethanol affect gluconeogenesis
pyruvate + NADH Lactate + NAD+
ethanol metabolism increases [NADH]
increased [NADH] pushes equilibrium towards lactate
lactate cannot be converted to glucose
= hunger because of low gluconeogenesis
shows how metabolism of xenobiotic changes internal pathways
examples of metabolic intergration
- changes following eating a meal
- changes during prolonged exercise
- diseases e.g T1D
- changes during starvation
why does body adapt to starvation
metabolic adaption must occur because of lack of nutrition and body has constatn requirement for energy to function
metabolic adaptation to starvation
- use of stored energy; glucose in blood, glycogen and TAG
- absolute requirements for glucose
- synthesis of ketone bodies
how are absolute requirements for glucose in starvation met
gluconeogenesis
proteolysis to provide precursors for gluconeogenesis
what can only use glucose as energy source
RBC
Simpe explanation of ketone bodie synthesis
- increase in beta oxidation of FA = acetyl CoA accumulation
- synthesis of beta-hydroxybutyrate and acetoacetate
- ketone bodies metabolised by brain instead of glucse
stages of starvation
0-18hrs after eating: glycogenolytic state
18-48hrs after eating: gluconeogenic state, using AA
2-40 days after eating: ketogenic state
changes in [blood glucose] from 1 day no eating to 20 days no eating
very little change
slowly drops from 4.2mM to 3.5mM
changes in [FFA] from 1 day no eating to 20 days no eating
slowly increases from 0.5mM to 1.5mM
changes in [ketone bodies] from 1 day no eating to 20 days no eating
dramatic increase from 0.1mM to 7mM
changes in [lactate] from 1 day no eating to 20 days no eating
stays constant, 0.75mM
what metablite shows a dramatic increase during starvation
ketone bodies, 0.1mM to 7mM
what metabolite shows no change during starvation
lactate, remains at 0.75mM
what metabolite has a slow increase during starvation
FFA, 0.5 to 1.5mM
what metabolite shows little change during starvation
glucose, 4.2mM to 3.5mM
brain metabolism during starvation
switches to metabolism of ketone bodies to reserve glucose for RBC
- increase in [ketone bodies] causes swtich
- ketone bodies can cross the BBB
- once in brain, converted back to acetyl CoA
- increase in acetyl CoA allosterically inhibits pyruvate dehydrogenase
= CHO metbolism is blocked
how is CHO metabolism in the brain blocked during starvation
increase in acetyl CoA allosterically inhibits pyruvate dehydrogenase
pyruvate cannot be converted to acetyl-CoA
= CHO metabolism blocked and glucose saved for RBC
metabolic actions of fed state liver
glycogen synthesis
glycolysis
FA synthesis
metabolic actions of starved state liver
glycogen breakdown
gluconeogenesis
ketogenesis
protein breakdown
what changes liver’s actions from fed to starvd state
- phosphorylation of enzymes
- allosteric regulation
- substrate availablity
- increased amounts of enzymes
liver changes in starvation: phosphorylation of enzymes
glycogen synthase inactivated by phosphorylation
glycogen phosphorylase activated by phosphorylation
metabolic changes on pre-existing enzymes = instant
liver changes in starvation: allosteric regulation
accumulation of acetyl coa
- stimulates pyruvate carboxylase
- inhibits pyruvate dehydrogenase
liver changes in starvation: substrate availabilty
ketogenesis increases when FA in blood increases
liver changes in starvation: increased amount of enzymes
because of gene expression = long term adaptation, fixed changes
- ketogenesis
- FA oxidation
- glucogeogenesis
phosphorylation of enzymes
a rapid response in seconds, a hormone stimulated cascade
- glucagon binds to receptor
- activates adenylate cyclase = increase in cAMP
- activaation of cAMP dependent protein kinase
= phosphorylation of target enzymes
= amplified signal
example of phosphorylatin of enzymes
Phosphodiesterase
- signalling response induced by hormones binding to receptor = short lived
- secondary messengers are degraded
- tea and caffeine inhibit phosphodiesterase causing levels of cAMP to remain high for longer
phosphodiesterase cAMP ----------------------> AMP
difference between short term and long term enzyme response to starvation
short term: induced by hormones binding to receptor. changes in expression of enzymes already present. short lived response
long term: altered gene expression, giving fixed changes
allosteric regulation of pyruvate carboxylase
- activated by acetyl CoA
= increased oxaloacetate formation
= increased rate of gluconeogenesis
allosteric regualtion of pyruvate dehydrogenase
- inactivated by acetyl CoA
- decreased rate of acetyl CoA from pyruvate
- pyruvate is saved for gluconeogenesis for RBC
- increased rate of gluconeogenesis
what is the speed of allosteric regulation response
rapid. seconds/minutes - just needs Acetyl CoA to accumulate
what is used as fuel sourc ein the gluconeogenic phase (18-48hrs starvation)
Amino acids
how can free AA be used to synthesise glucose
AA is a carbon skeleton and amino group
- can enter TCA directly or provide glycolytic intermediates
AA providing glycolytic intermediates
Alanine -> pyruvate + NH2
glutamate -> alpha-ketoglutarate + NH2
aspartate -> oxaloacetate + NH2
what AA forms pyruvate
alanine
what AA forms alpha ketoglutarate
glutamate
what AA forms oxaloacetate
aspartate
why does protein loss occur during starvation
protein turnover occurs 24/7, with proteins being proken to AA hen resynthesised
- if AA start to be used for gluconeogenesis, that cannot be used to resynthesis protein
what stops net proteolysis from occurs
increased FA oxiation causing increased acetyl coA
- acetyl coa allosterically blocks pyruvate dehydrogenase
- pyruvate isnt broken down and isntead used for gluconeogenesis
- pyruvate comes from glycolysis in RBC and not from alanine
= protein saved
what discourages formation of CHO from AA
CHO groups from AA cannot be metabolised from acetyl CoA in the TCA cycle
what increases protein metabolism in long-term starvation
increased cortisol levels
- occurs when glycogen, FA and TAG are all used up
how does increased cortisol stimulate protein metabolism in long term starvation
cortisol increases the expression of proteins and enzymes involved in the ubiquitin/proteomsome system
what substrates are increased during starvation
- fatty acid
- ketone bodies
why are fatty acid availabilty increase ins tarvation
increase in beta oxidation in the liver increases the concentration of acetyl coa
= triggers ketogenesis
why are ketone bodies increased in starvation
- able to cross the BBB when FA cant
- metablised by neurones
- increases the level of acetyle CoA
= allosteric blocking of CHO metabolism
how does prolonged starvation change enzyme exprsssion
changes in gene transcription
- mediated via peroxisome proliferator acitvated receptor (PPAR alpha)
- increased FA binds to PPAR
- PPAR activates transcription of enzymes involved in:
- FA oxidation
- Fa transport
- ketogenesis
PPAR alpha
peroxisome proliferator acitvated receptor
what activates transciption of anabolic enzymes during prolonged starvation
PPAR alpha
what signals to PPAR alpha during prolonged starvation
increased FA binding to PPAR
what increases the expression of gluconeogenesis enzymes during prolonged starvation
cortisol and glucagon
BMR
basal metabolic rate
minimum energy required for normal function in resting state
how does BMR change during starvation
usually, T4 stimulates gene expression, and contains iodine in its active site, from the diet - starvation = reduced iodine - T4 levels decrease - less enzymes are synthesised by TH = BMR reduced
LONG TERM
short term metabolic changes e.g overnight fast
changes in the activity of pre-existing enzymes
- phosphorylation
- allosteric regulation
long term metabolic changes e.g prolonged period of starvation
changes occur after a long period but also remain for a long time afterwards
= changes in amounts of enzymes from gene transcipion
- PPAR alpha
- T4 changing BMR
