5 - Maintenance of homeostasis by the liver Flashcards
What is metabolic flux?
The rate of flow of metabolites through and between pathways
How are the following regulatory mechanisms achieved?
1) Making new molecules and destroying old ones (changes in metabolic capacity and capability)
2) Changing the activities of existing molecules
3) Catalysis, often at irreversible steps.
1) governed by changes in gene expression
2) governed by covalent modification and allosteric interactions.
3) governed by ATP and or a transport step etc.
What are the 5 mechanisms coordinated by the liver that allow homeostasis?
1) Compartmentation within cells/tissues
2) Substrate availability
3) Allosteric effectors
4) Covalent modification
5) Induction of enzymes (gene expression)
Give some examples of metabolic compartmentation:
a) within tissues
b) within cells
a) Tissues:
Muscle (red and white fibres)
Liver - periportal and perivenous hepatocytes
Nervous systrem - neurones and glia
Kidney - cortex and medulla
b) Cells
Fatty acids (synth in cytosol, degraded in mitochondria)
Carbohydrates (stored in glycogen particles, synth and degraded in cytosol)
Rare CPT1 deficiency is associated with impaired ability to oxidise fats for energy.
Describe how compartmentation is achieved in fatty acid synthesis vs oxidation.
Preferably with a diagram.
- Fatty acyl-coA for oxidation is transported into mitochondria
- Membrane is impermeable to coA group
- Fatty acyl grop is transferred to carnitine by CPT1/CAT1
- On the matrix side, CPT2 converts this back to an anyl-coA for oxidation
- Manobyl coA tightly regulates allosteric activity of CPT1
What is the name for the process in which factors that switch on one pathway switch off the other.
Give an example of this
Reciprocal control
Glycolysis vs Gluconeogenesis
What is the first committed step in
fat synthesis
glycolysis
fat - manolyl coA
glycolosis - phosphofructokinase
what is the dominant allosteric regulator of glycolysis/glucoengensis
Fructose-2,6-P
What is the dominant committed and irreversible stage of glycolysis
The conversion of F-6-P to F-1,6-P
In the anabolic state
F-2,6-P is produced under conditions where F-6-P levels are ___, binding of the this to ___ significantly increases its catalysis of the formation of F1-6-P (increasing ___ and lowering the __). Conversely, binding to ____ has the opposite effects, increasing its __ for F-1,6-P and decreasing the ____. This step is also regulated by allosteric binding of ____ (produced at higher levels under a ______ and ______ state).
F-2,6-P is produced under conditions where F-6-P levels are high, binding of the this to PFK significantly increases its catalysis of the formation of F1-6-P (increasing Vmax and lowering the Km). Conversely, binding to FBPase has the opposite effects, increasing its Km for F-1,6-P and decreasing the Vmax. This step is also regulated by allosteric binding of citrate (produced at higher levels under a glycolytic and lipogenic state).
In an anabolic/well fed state
High glucose concentrations also stimulate ______ synthesis (although the primary regulation of this step is the hormonal regulation of the covalent modification [______] of _____ synthase). High [citrate] promote _____ synthesis, the first of these steps produces _______ which inhibits CPT-1 and prevents _____ oxidation, thus the pathways of fat utilisation remain _______.
High glucose concentrations also stimulate glycogen synthesis (although the primary regulation of this step is the hormonal regulation of the covalent modification [phosphorylation] of glycogen synthase). High [citrate] promote fatty acid synthesis, the first of these steps produces malonyl co-A which inhibits CPT-1 and prevents fatty acid oxidation, thus the pathways of fat utilisation remain lipogenic.
Feedforward stimulation
Binding of F-2,6-BP increases the affinity of ___ for _______.
A shift in the kinetics (sigmoidal to ______) representing an _______ in enzyme affinity.
Feedforward stimulation
Binding of F-2,6-BP increases the affinity of PFK for fructose-6.
A shift in the kinetics (sigmoidal to hyperbolic) representing an increase in enzyme affinity.
Feedback inhibition
High levels of ATP reduce affinity of ___ for Fructose-6-P
In muscle this effect is increased by ____ pH
In muscle and liver this is also _____ by citrate
Feedback inhibition
High levels of ATP reduce affinity of PFK for Fructose-6-P
In muscle this effect is increased by lower pH
In muscle and liver this is also increased by citrate
Under fasting conditions, _____ genesis becomes active; primarily hormonal control is exerted by an increase in ____:_____. Substrate levels also increase rate of ______ vs ______.
Under fasting conditions, gluconegenesis becomes active; primarily hormonal control is exerted by an increase in glucagon:insulin. Substrate levels also increase rate of gluconeogensis vs glycolysis.
Under fasting conditions: Increased muscle and tissue utilisation of glycogen stores (and ____ supplied by liver) increases ____ output of tissues and muscle, providing _____ as a substrate to the liver. Lactate is converted to ____ by ___. _____ enters mitochondria and is converted to ______ by __________ (located only in the mitochondria). ______ is transported to the cytosol via conversion to malate and _____ and back to _______ in the cytosol. _______ is converted to phosphoenolpyruvate by ______ which enters gluconeogensis.
Increased muscle and tissue utilisation of glycogen stores (and glucose supplied by liver) increases lactate output of tissues and muscle, providing lactate as a substrate to the liver. Lactate is converted to pyruvate by LDH. Pyruvate enters mitochondria and is converted to oxaloacetate by pyruvate carboxy kinase (located only in the mitochondria). Oxaloacetate is transported to the cytosol via conversion to malate and aspartate and back to oxaloacetate in the cytosol. Oxaolacetate is converted to phosphoenolpyruvate by PEPCK which enters gluconeogensis.
