Lipids 6: Fatty Acid Metabolism III Flashcards
How is macronutrient utilization regulated?
to foster oxidation of fuels abundant at the time and/or that cannot be stored which is typically between glucose and FAs
* Most tissues oxidize glucose in the postprandial/fed state and FAs in the fasted/starved state
What is the premise of the Randle cycle?
Glucose-Fatty Acid Cycle
Utilization of Glc ↓ with ↑ Acetyl CoA due to ↑ TG breakdown/ when we oxidzie fat we inhibit glucose oxidation
* Increased provision of exogenous lipid fuels or the increased breakdown of endogenous triacylglycerol stores promotes the use of lipid fuels &, in so doing, blocks the utilization of glucose.
What happens in the Randle Cycle during the fed and fasting states?
- During the fed state FAs go down and so muscle sees less FA being supplied since presence of insulin inhibits mobilization
- During fasting glucose levels drop and glucagon goes up so adipose releases FAs into blood supply, insulin is low so less glucose being transported into muscle and more β-oxidation in muscle occurs inhibiting glucose metabolism
Contribution of CHO vs. Lipid fuel utilization during exercise
Contribtuion of CHO vs. lipid fuel utilization during fasting/ starvation
What is metabolic flexibility?
Most tissues can use either Glucose or FAs as fuels, responding to changes in nutrient availability
Why can glucose not be used for energy with increased acetyl CoA from β-oxidation?
The increased Acetyl-CoA from TG hydrolysis
* inhibits the PDH complex so pyruvate cannot be turned to Acetyl-CoA in the mito inhibiting glucose from being used for energy
* activates pyruvate carboxylase so pyruvate is instead used to make glucose in the liver in order to conserve glucose and in muscle it is converted to lactate or alanine
What happens with Malonyl CoA during fed/fasting?
- Fed: Malonyl CoA from ACC reaction inhibits FA oxidation via CPT-1
- Fasting: Malonyl CoA levels decrease during fasting thus removing the inhibition of CPT1
Where are FAs oxidized?
FAs from plasma or mobilization of stored TG are oxidized in mitochondria
What does the rate of oxidation depend on?
substrate availability which is regulated by malonyl CoA
How are FAs ‘primed’ for oxidation?
by thiokinases (cytosol)
* Acyl-CoA synthases on ER & outer mitochondrial membranes catalyze activation of long chain FAs, esterifying them to coenzyme A (requires ATP)
* Fatty acyl CoAs → acyl carnitine (CPT1) → enter mitochondria via carnitine translocase → converted back to fatty acyl CoAs (CPT2) →enter β-oxidation
General steps of fatty acid oxidation (saturated, even chain length, palmitate)
- oxidize: Removal of 2 hydrogens between 2nd & 3rd C from CoA attachment C #; makes FADH supplying 2 e- to ETC
- hydrate: Water added across dbl bond
- oxidize: Removal of hydrogens; makes NADH supplying 3 e- to ETC
- cleave: Cleavage of terminal acetyl-CoA group (thiolysis reaction) with CoA → new acyl- CoA (2 Cs shorter)
oxidation of odd-chain fatty acids
Basically the same as the longer chain fatty acids but the final end products are 1 acetyl-CoA + Propionyl-CoA
* propionyl-CoA can be converted to Succinyl which can enter CAC and be used for making glucose
Oxidation of medium chain fatty acids
- Use different acyl-CoA dehydrogenases but otherwise oxidation uses the same steps
- main difference is that they do not require CPT1 to get into mitochondria
Oxidation of unsaturated fatty acids
For each double bond, one fatty acyl CoA dehydrogenase reaction is not required
* The double bond normally added is already present in the unsaturated FA
* Energy produced is less from an USFA than from an equal C-length SFA since FADH2 is not produced therfore 2 less ATPs per double bond
How much ATP is produced from the oxidation of palmitic acid?
Fatty acid oxidation is…
highly exothermic → generation of metabolic energy
Energy yields of CHO vs. lipids
0.5 glucose
backbone is glucoenogenic, but is only 3 carbons of the total 6 for glucose
Role of brown adipocytes
Does a lot of fatty acid oxidation but not for energy, it functions in thermogenesis (heat production) so does not store fat it burns fat through the uncoupling of oxidative phosphorylations via UCPs in the mito membrane
Mostly babies
mosEconomics of fasting when a person draws on stores during regular feeding schedule
Mostly draws on glycogen and fat stores
Economics of fasting if the fast continues beyond glycogen depletion
starts to break down proteins and fats converted to ketone bodies
What are ketones used for?
energy source for the body during long periods of fasting or very low carbohydrate intake which allows cardiac & skeletal muscle to further reduce glucose oxidation and can preserve plasma glucose for the brain
What are the 2 main ketoacids in plasma?
- Acetoacetate
- β-Hydroxybutyrate
ketone body production under normal conditions
occurs at a relatively low rate
ketone production under CHO deficit (fasting or very-low CHO diet)
- ↑ fatty acid oxidation occurs in the liver
- ↑ Acetyl-CoA production
- ↑ production of ketone bodies
How are ketones used by the brain?
reliable source of energy during fasting that can partly replace glc as a fuel
Why can’t the brain use FAs as a fuel source?
FAs are bound to albumin in plasma and cannot freely traverse the BBB, so FAs themselves cannot be used for energy
Why can the liver not use ketones for energy?
Enzyme that activates ketone bodies for use as energy is not present to avoid futile cycling
* role in ketogenesis but not ketolysis
Where does ketone body synthesis occur?
in the mitochondria of the hepatocytes
What is the rate of ketone bodies coupled to?
The rate of FA oxidation
What is made when ketone levels are super high?
Acetone
* diabetic ketoacidosis/ starvation
* can be smelled on breath
When does ketone body utilization (ketolysis) occur
- during fasting
- certain diet conditions
Where does ketolysis occur?
non-hepatic tissues that have the enzyme β-ketoacyl-CoA transferase (SCOT)
* brain, heart, skeletal muscle
* occurs in the cytosol in reversal of ketone body synthesis
Concentration of ketone bodies & plasma FFAs over time
Use of Ketones as fuels by extrahepatic tissues is proportional to their availability
What is the most profound clinical manifestation of ketogenesis?
Diabetic Ketoacidosis occuring in Type 1 diabetes mellitus which causes acidification of blood and can be dangerous by imparing the ability of Hb to bond oxygen
* ↓ GLC uptake (↓ insulin) → ↑ FA oxidation (↑ glucagon) → ↑ Acetyl-CoA production → ↑ketone body production →exceeds oxidation capacity of peripheral tissues → ↑↑ plasma ketones (acidic) → ↓ pH of plasma
