Fatty Acid Oxidation Flashcards
What is happening big picture in beta oxidation
Going from storage situation to breaking down fatty acids for mobilization for energy
What kind of fatty acids are the major fuel store for the body
TAG
What two enzymes releases fatty acids from TAG (from adipose)
Which one is more important
Main difference in why this is the case?
Adipose lipoase and hormone sensitive lipase
Hormone sensitive lipase
HSL cannot be re-esterified (more set in stone); adipose lipase can be re-esterified
What activates HSL
Epinephrine and glucagon (because it is specifically activated by cAMP dependent protein kinases - think cell signaling lecture)
~What does lipoprotein lipase do
Releases FAs from TAG in circulating lipoproteins to FFAs and glycerol
When HSL is activated, what does it bind to
Perilipin (lipid droplet surface protein)
When HSL is activated, what does it do
It helps with the phosphorylation of ACC in order to inactivate it and turn off fatty acid synthesis
~side note: insulin will do opposite; dephosphorylate HSL to make it inactivate and activate ACC when fatty acid synthesis needs to happen again
When TAG is degraded, where does the glycerol from it go?
Has to go to liver, not adipose because liver has glycerol kinase and adipose does not. (Adipose cannot do anything with glycerol once it is removed from FAs and not in TAG form)
~TAG= glycerol + FAs~
What happens to glycerol when it is brought to the liver
1 of 2 things:
Phosphorylated in the liver to be used for TAG synthesis
Reversibly converted to DHAP (by glyercol phosphate dehydrogenase); DHAP can participate in glycolysis or gluconeogenesis
(In between meals - goes to glycolysis; deep into fasting - goes to gluconeogenesis)
What two organs do not use fatty acids for energy
RBCs (no mitochondria) and brain
About half the the FFAs released from adipose TAG are re-esterified to?
Clinical significance?
Glycerol-3-phosphate
Decreases plasma FFA associated with insulin resistance in type 2 diabetes and obesity
3 products of beta oxidation
Acetyl CoA, NADH, FADH2
~NADH and FADH2 can feed right into ETC
How does our body obtain carnitine (2 ways)
Diet: mostly meat products
Synthesized: in liver/kidney only using lysine and methionine
Where is majority of carnitine housed in the body?
Skeletal muscle
Carnitine deficiency would affect what?
The ability of tissues to use LCFA as a metabolic fuel
Secondary carnitine deficiencies are caused by
Decreased synthesis due to liver disease, dietary malnutrition, hemodialysis, or conditions where your body needs more carnitine (pregnancy, infections, burns, trauma)
Primary carnitine deficiencies are caused by congenital deficiencies in what two things?
Renal tubular reabsorption of carnitine; or carnitine uptake by cells
CAT1 genetic defect?
Decreased liver use of LCFA during a fast (severe hypoglycemia, coma, death)
CAT II genetic defect?
Heart and skeletal muscle exhibit the symptoms following prolonged exercise (cardiomyopathy, muscle weakness, myoglobinemia)
Treatment for both CAT I and II deficiencies
Avoid fasting, eat high carbs and low LCFA, supplement with carnitine and medium chain fatty acids
Short/medium chain fatty acids do not need CAT 1 or 2. How do they get converted?
Thiokinase (so malonyl CoA has no effect because you don’t need CAT1)
How is beta oxidation linked to gluconeogenesis
Acetyl CoA is a positive allosteric effector of pyruvate carboxylase
How many ATPs are produced from beta oxidation
129 ATP
What is different about beta oxidation of an odd number carbon fatty acid chain?
Similar except the final cleavage produces a 3 carbon product: propionyl CoA (not acetyl CoA)
3 steps for metabolism of propionyl CoA
- Propionyl CoA is carboxylated by propionyl CoA carboxylase (ABC enzyme*)
- D methylmalonyl CoA -> L methylmalonyl CoA (isomerization)
- Carbons from L-methylmalonyl CoA are rearranged to form succinyl CoA by methylmalonyl CoA mutase to enter TCA
Which two enzymes from the last slide (metabolism of propionyl CoA) require vitamin B12
So vitamin B12 deficiency leads to?
Propionyl CoA carboxylase and methylmalonyl CoA mutase
Metabolic acidosis and potential mental retardation
Difference in beta oxidation of saturated vs unsaturated fatty acids
Unsaturated release less energy
Mono and poly require additional enzymes for complete oxidation
Where are very long chain fatty acids beta oxidized?
Peroxisomes (does not generate ATP)
- Zellweger syndrome?
- X linked adrenoleukodystrophy?
- Both disorders lead to?
- Failure to deliver correct enzymes to peroxisomes
- Cannot transport VLCFA across the peroxisome membrane
- Accumulation of VLCFAs in the blood/tissue
Difference between alpha and beta oxidation
Alpha: acyl CoA dehydrogenase cannot work on the substrate so alpha oxidation uses PhyH instead
What disease is caused by PhyH deficiency?
Refsum (rare) symptoms are mostly neurologic - treat with dietary restrictions
- What is MCAD
- Symptoms
- Treatment
- Deficiency in fatty acyl CoA dehydrogenase
- Severe hypoglycemia
- Avoid fasting
Where are ketone bodies formed?
Liver mitochondria
3 metabolic products of ketone bodies
Acetoacetate, 3-hydroxybutyrate, and acetone (acetone is dead end product)
When would liver produce ketones?
When acetyl CoA levels are higher than oxidation capacity
What part of body mainly uses ketones?
Skeletal muscles (RBCs cannot use ketones- no mitochondria)
What two symptoms would you get if you had a disorder in being able to do fatty acid oxidation
- Hypoketosis - due to decreased acetyl CoA availability
2. Hypoglycemia- due to increased reliance on glucose for energy
If you have high hepatic acetyl CoA, what enzyme will get inhibited and what enzyme will get activated?
Inhibited: pyruvate dehydrogenase
Activated: pyruvate carboxylase
Pyruvate carboxylase produces __ which is used in what pathway?
OAA - gluconeogenesis also for ketone body synthesis
How does OAA get shifted to do ketogenesis opposed to gluconeogenesis?
Beta oxidation leads to acetyl CoA, NADH, and FADH2. Acetyl CoA leads to formation of OAA and increased levels of NADH lead OAA to be converted to Malate.
Formation of malate is what shifts acetyl CoA from gluconeogenesis and form ketogenesis
What is the rate limiting step in ketogenesis? Where is this enzyme present?
HMG CoA synthase - present in the liver in significant amounts
Main takeaway from steps of ketogenesis
HMG CoA is substrate for producing acetoacetate (ketones)
HMG CoA was produced from reverse of thiokinase reaction in beta oxidation
Ketolysis: using ketone bodies
- 3-hydroxybutyrate is oxidized to acetoacetate and this produces?
- Next 2 steps?
- NADH in peripheral tissues
2. Acetoacetate takes CoA from succinyl CoA; acetoacetyl CoA is converted to 2 acetyl CoA
Why can’t liver use ketone bodies as fuel?
Liver lacks thiphorase
Why does ketonemia and ketouria happen in uncontrolled type I diabetes?
Body thinks you are starving because insulin is not being produced so ketone bodies are made. But since there is actually glucose in the blood the ketone bodies produced are not used so they build up
Diabetic ketoacidosis causes?
Fruity smelling breath from acetone, increased secretion of water and dehydration, lower blood pH (ketones are acidic)
