Lecture 10 - Cardiac metabolism Flashcards
The myocardium is highly ______ and has a preference for _________
Myocardium is highly oxidative and has a preference or fatty acids
>90% of it’s energy is produced by mitochondrial respiration, each cardiac muscle cell is packed with mitochondria
Describe the changes in carbohydrate and lipid metabolism in the heart from the fetal state to adult, exercising conditions, and also in diabetic and fasting people.
Fetal state: the fetal heart gets the majority of it’s energy from carbohydrates since the foetus is in a hyperinsulaemic state, which promotes glycolysis. The pO2 is also low, and since lipid metabolism via beta oxidation requires more O2 the foetus is better suited to get most of it’s energy for the heart via glycolytic pathway.
When they’re born, their pO2 goes up so there is a shift from carbohydrate to lipid metabolism for energy (Shift from primarily glyocolyis pathway to beta oxidation).
Adult: More energy is obtained from beta oxidation than glycolysis to generate ATP for the heart.
Ichaemic heart: In the failing heart it shifts to using more carbohydrates (since less O2 is available for beta oxidation). This also happens in a heart during exercise for the same reason. This is why exercise is cardioprotective, since it’s involved pathways that are protective in an ischaemic patient.
Fasting and diabetic state: In a fasting and diabetic state you are more dependant on lipids. Since in diabetes and fasting you are pretty much starving cells of glucose - so the heart ends up doing beta oxidation.
Why is diabetes a risk factor for ischaemia?
Since in diabetes it causes the heart metoblism to use mainly beta oxidation for energy (due to not being able to use glucose). This increases O2 consumption, and this predisposes a person for ischaemia.
What fuel is used by the heart in a fed state?
More glycolysis pathways using carbohydrates
Which fuel is used more by the heart in fasted and diabetic patients?
Primarily lipids
What is fuel utilisation by the heart determined by?
- Substrate concentration
- Lipids more when fasted, and carbs more when in fed state- due to availability of fuels.
- Hormones
- In fed state theres more insulin -> allows heart to use for carbohydrates for fuel
- In fasted state there’s more glucagon & hormone sensitive lipase. HSL (increased in activity by glucagon and insulin) mobilises TAGs to FFAs, therefore lipids are used more as a source in fasted state.
- O2 availability
- If more O2 is available due to resting etc, more beta oxidation can be used. But if exercising, less O2 is available so more carbohydrate metabolism is used.
- Workload
Which produces more energy, beta-oxidation or glycolysis?
Beta oxidation. Since it produces more hydride ions that can enter the ETC to generate more ATP.
Therefore lipids being oxidised in beta-oxidation generates more ATP than carbohydrates being metabolised in glycolysis.
How is ATP generated in the ETC?
Complexes in the membrane get the hydride ions fom NADH and FADH2 and use the stored energy to pump H+ to create a proton gradient. The energy stored in this gradient is then used to make ATP.
How is glucose taken up into the cardiac cell?
Glucose is taken up by mutliple transport proteins GLUT4 and GLUT1.
GLUT4 - this glucose transporter is insulin responsive, the myocyte transports GLUT4 to the cell surface in response to insulin.
GLUT1 - It’s a glucose senstive glucose transporter, it’s not senstive to insulin
How are fatty acids taken up?
VLDL binds to the surface of a cardiac myocyte where it encounters LPL.
This enzyme breaks down the TAG into fatty acids and glycerol, the fatty acid gets acetylated and enters the cell.
In the fasted state HSL librates fatty acids from cells and attach to albumin. Albumin binds long chained fatty acids, which then binds to fatty acid trasporters, where they cross the membrae and become acetylated to become fatty acyl CoA.
For the FFA to get transported into the mitochondria it has to go across a carnitine shuttle to enter the mitochondria. The enzymes for beta oxidation are present here.
What are the cardiac metobolic concequences of diabetes?
Increased reliance on FA oxidation, and a decresaed reliance on carbohydrate oxidation.
What are the cardiac metabolic concequences on a hypertrophied heart?
Decrease in FA oxidation, increase in glycolysis
What are the cardiac metabolic concequences on a hypoxic heart?
Decrease in oxidative metabolism, increase in glycolysis
What are the cardiac metabolic conequences of a reperfused heart?
There is an increased reliance on fatty acid oxidation, and a decrease in reliance on carbohydrate oxidation
there are normal glyocolytic rates.
Why does fatty acid metabolism tend to stop carbohydrate metabolism?
There is negative feedback, where acetyl coA feeds back and prevents glucose metabolism.
When lots of carbs are metabolised ACC is made, this joins two acyl CoAs together to make malinyl CoA. Malinyl CoA binds to carnitine transport and shuts it off. So with the presence of this no shuttling of fatty acyl CoA can occur since it stops the carnitine shuttle.
What is HIF and what does it do?
HIF = hydroxy induced factor.
When theres low O2, HIF1 is a transcription factor that binds to DNA and promotes the transcription of many different genes that are controlled by binding to HIF (since its a transcription factor).
The HIF genes promote glycolysis, glucose transport, PFK, LDH, reduce fatty acid oxidation and PPAR signaling.
It increases the expression of genes involved in glucose utilization
Under normal O2 conditions HIF gets hydroxylated, and then gets ubiquonated to signal that it needs to be recylced at the proteasome (since it’s not really needed)
