Amino acids that are only converted to Acetyl-CoA cannot contribute to gluconeogenesis, because
the conversion of pyruvate into Acetyl-CoA is irreversible. Amino acids that are converted to the
intermediates of the Krebs cycle (like oxaloacetate) can contribute to gluconeogenesis, because 2
carbons (2 CO2) are lost. Fatty acids are mostly converted to Acetyl-CoA and can therefore not
contribute to gluconeogenesis.
Prolonged starvation: save the protein → go to ketone production
- ketones are water-soluble enough to cross the blood-brain barrier and allow us to produce ATP
(brain)
Glucagon ↑, insulin ↓ → stimulates body to start breaking down fatty acids (fatty acid oxidation, in
the liver) → Acetyl-CoA molecules → Krebs cycle → electron transport chain → ATP
- overshoot of Acetyl-CoA production (after 3-4 days), because there is no type of product inhibition
(regulation) → more ATP production → reports back to ETC to slow down → NADH ↑ → slows down
Krebs cycle → shunt Acetyl-CoA to the production of ketones (in liver to brain)
- rate of protein degradation goes down due to shift to ketone production
All cellular processes require energy: the mitochondria are involved in generating energy
- protein/RNA/molecule/DNA synthesis
- transport of all kind of things
- DNA repair
- almost all processes require energy
ATP is the currency of energy in the cell
The pathways involved in generating energy
- glycolysis (glucose to pyruvate)
- citric acid cycle
- electron transport chain (via proton gradient)
- fatty acid (or beta) oxidation → fatty acids are long chains of carbons, cleave off and enter the CAC
- proteins broken down into amino acids (no oxidation in normal diet, but in excess of protein diet)
- ketones are produced by the liver from fat → used by the brain/heart/muscles (can be produced
during long term exercise)
Glycolysis
- glucose 6-phosphate cannot leave the cell
Regulation steps:
- negative feedback from glucose 6-P to hexokinase
- high energy charge negatively regulates PFK and pyruvate kinase
- low energy charge positively regulates (stimulates) PFK and feedforward stimulation of pyruvate
kinase by fructose 1,6-bisphosphate
,Pyruvate is transported into mitochondria, converted into acetyl CoA by
pyruvate dehydrogenase (PDH), and enters the citric acid cycle
Coupling of citric acid cycle with
oxidative phosphorylation generates
ATP
Which/how are nutrients mobilized
during exercise?
- fatty acids
- glycogen (stored in muscles, stores
can be depleted during long exercise)
- ketones (during long term exercise,
not really skeleton muscles, but the heart)
Intramuscular and extramuscular fuel sources
for exercise
- regulation: metabolic demand
allosteric regulation
nutrient sensors (AMPK)
bioactive peptides (epinephrine,
myokines)
Most of your energy is stored in the adipose
tissue, supporting the muscle
- backbone of the triglycerides can be used for energy
- during heavy exercise lactate is produced by the muscle and transported to the liver (where it is
converted back into glucose)
,Glucose can be transported through the blood
- lipids are hydrophobic and cannot be transported easily through the blood → lipoprotein particles
→ chylomicron (hydrophilic outside, triglycerides/cholesterol/ADK/vitamins inside) (intestine to the
fat tissue is chylomicron)
- VLDL particles (produced in the liver) is a way to regulate/control the fat pathway
- LDL (low density (smaller), more cholesterol, considered bad) in the blood is more a risk factor for
atherosclerosis → are taken up by the liver and converted into VLDL
- oxidation of LDL → macrophages → plaque formation (atherosclerosis)
- HDL (considered the good cholesterol) takes up cholesterol → efflux the oxidation of LDL → normal
(not foam) macrophages
Fasted state
- substrate switch from glucose to fatty acid oxidation
- glycogenolysis (short fast): breakdown of glycogen
- gluconeogenesis (long fast): make glucose
, METABOLIC FLEXIBILITY IN HEALTH AND DISEASE
Metabolic flexibility: the adaptive response of metabolism to maintain energy homeostasis by
matching fuel availability and demand
- flexibility of your cell to adapt to the environment → each cell has metabolic flexibility
fed state: cell prefers glucose
fasted state: cell prefers fatty acid oxidation
Human physiology evolved during times of fluctuations in energy supply and demand
- our energy metabolism adapted to obtain optimal substrate storage and use during combinations
of: food surplus, famine, rest, activity, infections
Fed state
- pyruvate dehydrogenase converts pyruvate into Acetyl-CoA
- excess of Acetyl-CoA (during fed state) → increase malonyl-CoA → blocks transporter of fats →
reduced fatty acid oxidation
- increase pyruvate → inhibits PDK → stimulates glucose oxidation
Fasted state
- glucose is not available to your muscle cell (if insulin drops)
- increase AMP/ATP → AMPK blocks ACC → blocks the formation of malonyl-CoA from
acetyl-CoA → inhibition of transporter (CPT-1) is gone → fatty acids are transported
into the mitochondria → beta oxidation → acetyl-CoA, NADH increase → inhibits PDH,
increase in citrate → reduced glucose uptake and oxidation
- citrate inhibits GLUT4 (glucose transporter) and PFK-1
Why is this switch important?
- you want to conserve glucose during the fasted state for your brain, which can only
use glucose for energy
- neurons need a lot of energy (spikes are a problem if you use FAs for their energy production)
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