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Metabolism > Metabolic integration > Flashcards

Metabolic integration Flashcards

1
Q

what is metabolic integration

A
  • interconnection of pathways
  • allows tissue differences
  • communication between tissues (hormones, metabolites)
  • inter-regulation of pathway (not always active)
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2
Q

key metabolic pathways

A
  • 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
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3
Q

example of tissue specific enzyme expression: ketone metabolism

A

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

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4
Q

most common ketone bodies

A
  • acetoacetate
  • beta-hydroxybutyrate
  • acetone
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5
Q

what is ketogenesis

A

formation of ketone bodies from fatty acids and amino acids

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6
Q

process of ketogenesis

A
  • 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
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7
Q

what can spontaneously happen to acetoacetate

A
  • break down to CO2 and acetone

- acetone CANNOT be converted back to acetyl CoA§

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8
Q

ketone oxidation

A
  • 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

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9
Q

example of tissue specific enzyme expression: glycogen metabolism

A

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

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10
Q

examples of glycogen storage diseases

A
  • Van Gierke’s disease

- McArdles desease

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11
Q

Van Gierke’s disease

A

glycogen storage disease

  • deficiency of liver G6P
  • fasting hypoglycaemia
  • unable to use liver glycogen to maintain glucose level
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12
Q

McArdles disease

A

glycogen storage disease

  • deficiency of muscle glycogen phosphorylase
  • unable to do prolonged exercise
  • unable to use muscle glycogen for energy
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13
Q

where does glycolysis occur

A

liver, muscle, adipose, brain, RBC

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14
Q

where does kreb cycle occur

A

liver, muscle, adipose, brain

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15
Q

where does beta oxidation of FA occur

A

liver, muscle, adipose

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16
Q

where does glycogen breakdown occur

A

liver and muscle

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17
Q

where does ketone body oxidation occur

A

muscle and brain, conditionally

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18
Q

where organ is considered the metabolic heart

A

liver

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19
Q

where do all the main anabolic processes occur

A

liver

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20
Q

differential regualtion

A

happen at different times

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21
Q

differential regulation of glycogen metabolism

A
  • 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

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22
Q

differential regulation of fatty acid metabolism

A

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

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23
Q

how do tissues communicate

A
  • metabolites in the blood
  • hormones in the blood
  • nervous signals from CNS
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24
Q

examples of blood metabolites for tissue communication

A

glucose
lactate
FA
ketone bodies

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25
Q

examples of hormones in the blood for tissue communication

A

insulin
glucagon
adrenaline
cortisol

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26
Q

examples of nervous signel from CNA for tissue communication

A

noradrenalne

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27
Q

Cori cycle

A

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

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28
Q

what is insulin produced in response to

A

high glucose

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29
Q

what is glucagon produced in response to

A

low glucose

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30
Q

hormonal control od metabolism reguated by

A

glucagon and insulin

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31
Q

levels of blood glucose, insulin and glucagon in the fasted state

A

low blood glucose
low insulin
high glucagon

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32
Q

levels of blood glucose, insulin and glucagon in the fed state

A

high blood glucose
high insulin
low glucagon

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33
Q

what processes increase and decrease in the liver in the fasted state

A

increased: gluconeogenesis, beta oxidation,
decreased: glycogen synthesis, FA synthesis, glycogenolysis

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34
Q

what happens in the muscle in fasted state

A

reduced glycogen synthesis

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35
Q

what happens in the adipose in fasted state

A

increases release of FA
decreases FA synthesis
decreased TAG synthesis, time dependent (not initially)

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36
Q

what processes increase and decrease in the liver in the fed state

A

increased: glycogen synthesis, beta oxidation, FA synthsis
decreased: gluconeogenesis, glycogenolysis

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37
Q

what happens in the muscle in fed state

A

increased glucose uptake and glycogen synthesis

decreased glycogen breakdown

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38
Q

what happens in the adipose in fed state

A

increased FA synthesis and glucose uptake

decrease FA release

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39
Q

xenobiotics

A

synthetics, not found in human cells

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40
Q

effect of xenobiotics on human metabolism

A
  • 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

41
Q

ethanol metabolism

A
  1. ethanol -> acetaldehyde
    enzyme: alcohol dehydrogenase, NAD+ -> NADH + H+
  2. acetaldehyde -> acetate
    enzyme: aldehyde dehydrogenase, NAD+ -> NADH +H+
42
Q

What does ethanol metabolism require

A

NAD+ as cofactor, which produced NADH and has consequences

43
Q

acetaldehyde

A

ethanAl

44
Q

pyruvate/lactate equilibrium

A

NADH + H+ ——-> NAD+
pyruvate lactate
NADH + H+ < ——- NAD+

enzyme: lactate dehydrogenase

increased NADH:NAD+ resutls in increased lactate:pyruvate

45
Q

why is lactate a dead-end molecule

A

only goes back to pyruvate, does nothing else

46
Q

how does ethanol affect gluconeogenesis

A

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

47
Q

examples of metabolic intergration

A
  • changes following eating a meal
  • changes during prolonged exercise
  • diseases e.g T1D
  • changes during starvation
48
Q

why does body adapt to starvation

A

metabolic adaption must occur because of lack of nutrition and body has constatn requirement for energy to function

49
Q

metabolic adaptation to starvation

A
  • use of stored energy; glucose in blood, glycogen and TAG
  • absolute requirements for glucose
  • synthesis of ketone bodies
50
Q

how are absolute requirements for glucose in starvation met

A

gluconeogenesis

proteolysis to provide precursors for gluconeogenesis

51
Q

what can only use glucose as energy source

A

RBC

52
Q

Simpe explanation of ketone bodie synthesis

A
  • increase in beta oxidation of FA = acetyl CoA accumulation
  • synthesis of beta-hydroxybutyrate and acetoacetate
  • ketone bodies metabolised by brain instead of glucse
53
Q

stages of starvation

A

0-18hrs after eating: glycogenolytic state
18-48hrs after eating: gluconeogenic state, using AA
2-40 days after eating: ketogenic state

54
Q

changes in [blood glucose] from 1 day no eating to 20 days no eating

A

very little change

slowly drops from 4.2mM to 3.5mM

55
Q

changes in [FFA] from 1 day no eating to 20 days no eating

A

slowly increases from 0.5mM to 1.5mM

56
Q

changes in [ketone bodies] from 1 day no eating to 20 days no eating

A

dramatic increase from 0.1mM to 7mM

57
Q

changes in [lactate] from 1 day no eating to 20 days no eating

A

stays constant, 0.75mM

58
Q

what metablite shows a dramatic increase during starvation

A

ketone bodies, 0.1mM to 7mM

59
Q

what metabolite shows no change during starvation

A

lactate, remains at 0.75mM

60
Q

what metabolite has a slow increase during starvation

A

FFA, 0.5 to 1.5mM

61
Q

what metabolite shows little change during starvation

A

glucose, 4.2mM to 3.5mM

62
Q

brain metabolism during starvation

A

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

63
Q

how is CHO metabolism in the brain blocked during starvation

A

increase in acetyl CoA allosterically inhibits pyruvate dehydrogenase
pyruvate cannot be converted to acetyl-CoA
= CHO metabolism blocked and glucose saved for RBC

64
Q

metabolic actions of fed state liver

A

glycogen synthesis
glycolysis
FA synthesis

65
Q

metabolic actions of starved state liver

A

glycogen breakdown
gluconeogenesis
ketogenesis
protein breakdown

66
Q

what changes liver’s actions from fed to starvd state

A
  • phosphorylation of enzymes
  • allosteric regulation
  • substrate availablity
  • increased amounts of enzymes
67
Q

liver changes in starvation: phosphorylation of enzymes

A

glycogen synthase inactivated by phosphorylation
glycogen phosphorylase activated by phosphorylation

metabolic changes on pre-existing enzymes = instant

68
Q

liver changes in starvation: allosteric regulation

A

accumulation of acetyl coa

  • stimulates pyruvate carboxylase
  • inhibits pyruvate dehydrogenase
69
Q

liver changes in starvation: substrate availabilty

A

ketogenesis increases when FA in blood increases

70
Q

liver changes in starvation: increased amount of enzymes

A

because of gene expression = long term adaptation, fixed changes

  • ketogenesis
  • FA oxidation
  • glucogeogenesis
71
Q

phosphorylation of enzymes

A

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

72
Q

example of phosphorylatin of enzymes

A

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
73
Q

difference between short term and long term enzyme response to starvation

A

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

74
Q

allosteric regulation of pyruvate carboxylase

A
  • activated by acetyl CoA
    = increased oxaloacetate formation
    = increased rate of gluconeogenesis
75
Q

allosteric regualtion of pyruvate dehydrogenase

A
  • inactivated by acetyl CoA
  • decreased rate of acetyl CoA from pyruvate
  • pyruvate is saved for gluconeogenesis for RBC
  • increased rate of gluconeogenesis
76
Q

what is the speed of allosteric regulation response

A

rapid. seconds/minutes - just needs Acetyl CoA to accumulate

77
Q

what is used as fuel sourc ein the gluconeogenic phase (18-48hrs starvation)

A

Amino acids

78
Q

how can free AA be used to synthesise glucose

A

AA is a carbon skeleton and amino group

- can enter TCA directly or provide glycolytic intermediates

79
Q

AA providing glycolytic intermediates

A

Alanine -> pyruvate + NH2
glutamate -> alpha-ketoglutarate + NH2
aspartate -> oxaloacetate + NH2

80
Q

what AA forms pyruvate

A

alanine

81
Q

what AA forms alpha ketoglutarate

A

glutamate

82
Q

what AA forms oxaloacetate

A

aspartate

83
Q

why does protein loss occur during starvation

A

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

84
Q

what stops net proteolysis from occurs

A

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

85
Q

what discourages formation of CHO from AA

A

CHO groups from AA cannot be metabolised from acetyl CoA in the TCA cycle

86
Q

what increases protein metabolism in long-term starvation

A

increased cortisol levels

- occurs when glycogen, FA and TAG are all used up

87
Q

how does increased cortisol stimulate protein metabolism in long term starvation

A

cortisol increases the expression of proteins and enzymes involved in the ubiquitin/proteomsome system

88
Q

what substrates are increased during starvation

A
  • fatty acid

- ketone bodies

89
Q

why are fatty acid availabilty increase ins tarvation

A

increase in beta oxidation in the liver increases the concentration of acetyl coa
= triggers ketogenesis

90
Q

why are ketone bodies increased in starvation

A
  • able to cross the BBB when FA cant
  • metablised by neurones
  • increases the level of acetyle CoA
    = allosteric blocking of CHO metabolism
91
Q

how does prolonged starvation change enzyme exprsssion

A

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
92
Q

PPAR alpha

A

peroxisome proliferator acitvated receptor

93
Q

what activates transciption of anabolic enzymes during prolonged starvation

A

PPAR alpha

94
Q

what signals to PPAR alpha during prolonged starvation

A

increased FA binding to PPAR

95
Q

what increases the expression of gluconeogenesis enzymes during prolonged starvation

A

cortisol and glucagon

96
Q

BMR

A

basal metabolic rate

minimum energy required for normal function in resting state

97
Q

how does BMR change during starvation

A 
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

98
Q

short term metabolic changes e.g overnight fast

A

changes in the activity of pre-existing enzymes

  • phosphorylation
  • allosteric regulation
99
Q

long term metabolic changes e.g prolonged period of starvation

A

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

Metabolism (11 decks)

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