beta-Oxidation & Ketone Body Metabolism Flashcards
1
Q
Where are trigylcerides stored? When are they triggered to be released? What are they released as?
A
- stored in adipocytes
- when blood glucose levels are low, hormones (cortisol and epinephrine) activate hormone-sensitive lipase
- hormone-sensitive lipase cleaves triglycerides into glycerol and free fatty acids, which are released into the blood
- (glycerol is H2O soluble, but fatty acids require albumin to traverse the blood)
2
Q
Which cells take up glycerol and fatty acids?
A
- the liver takes up glycerol to use it in gluconeogenesis (remember blood glucose levels are low!)
- fatty acids enter most cells, but many also enter the liver
3
Q
What happens to fatty acids in the liver?
A
- fatty acids undergo B-oxidation in the liver to form acetyl-CoA and ATP
4
Q
B-oxidation of fatty acids results in acetyl-CoA and ATP - what are these products used for?
A
- to power gluconeogenesis!
- gluconeogenesis requires ATP (and since this is occurring in the starved state, we need to get ATP from alternate sources); in addition, acetyl-CoA is needed to turn on pyruvate carboxylase, which begins gluconeogenesis
- the acetyl-CoA is then used for ketogenesis
5
Q
What’s the purpose of ketogenesis?
A
- ketogenesis generates ketone bodies, which leave the liver and enter the blood; they are rapidly taken up by starving muscle cells to be used as fuel
- (in prolonged starvation, ketone bodies are also used by the brain - this preserves the small amount of glucose to be used as fuel for the RBCs since they can ONLY use glucose)
6
Q
What’s happening in B-oxidation? What is it used for?
A
- B-oxidation moves high energy electrons from the beta-carbon (3rd carbon) of the fatty acid and uses it in the ETC to make ATP (in the liver this ATP is used to power gluconeogenesis, in other cells, this ATP is used for their own needs)
- B-oxidation also creates acetyl-CoA, which is used to create ketone bodies in the liver, and is used to create more ATP via the TCA cycle in other cells for their own needs
7
Q
Where does B-oxidation take place? How do fatty acids enter this site?
A
- occurs in the mitochondrial matrix (so any cell with mitochondria can generate ATP via B-oxidation; again, RBCs lack mitochondria so they can NOT)
- 1) fatty acids diffuse from the cytoplasm into the outer mitochondrial membrane, where it is attached to a CoA to form FA-CoA (this requires an enzyme, CoA, and ATP)
- 2) FA-CoA then becomes FA-carnitine via carnitine acyltransferase-1 (CAT-1)
- 3) FA-carnitine enters the matrix via carnitine transporters in the inner mitochondrial membrane
- 4) in the matrix, FA-carnitine is returned to FA-CoA via CAT-2
8
Q
Now, we know fatty acids are synthesized in the cytoplasm, so what prevents these fatty acids from constantly being shuttled into the mitochondria to be burned off?
A
- basically, when fatty acid synthesis is occurring, B-oxidation is inhibited and vice-versa
- carnitine acyltransferase-1 (CAT-1) is inhibited by malonyl-CoA, which is a product of fatty acid synthesis
9
Q
What happens to FA-CoA once it’s in the mitochondrial matrix?
A
- B-oxidation!
- fatty acyl-CoA dehydrogenase transfers electrons from the B-carbon to FAD to form FADH2
- another enzyme then transfers more electrons to NAD to form NADH, generating a shorter FA-CoA + acetyl-CoA
- (these activated carriers transfer electrons to the ETC to generate 5 ATP)
10
Q
How many carbons are involved in one cycle of B-oxidation? What does one cycle generate?
A
- 2 carbons are involved
- for every 2 carbons: 1 FADH2, 1 NADH, and 1 acetyl-CoA
- each cycle shortens the FA-CoA by 2 carbons, and the process repeats itself until the FA-CoA is 4 carbons long, where it will go through one more cycle to generate 1 FADH2, 1 NADH, and 2 acetyl-CoA
11
Q
What is myopathic CAT deficiency? What other pathology does it strongly resemble? How can we tell the difference between the two?
A
- defective CAT-1, carnitine transport, or CAT-2, resulting in muscle aches, weakness, myoglobinuria, etc.
- (it’s myopathic, because muscles are the most affected due to their high energy demand)
- strongly resembles McArdle disease (glycogen storage disease type V); take a muscle biopsy to differentiate between the two: increased triglycerides in the cytoplasm indicate CAT deficiency, increased glycogen in the cytoplasm indicates McArdle disease
12
Q
Fatty acyl-CoA dehydrogenase
A
- involved in the first step of B-oxidation
- many isoforms to deal with different lengths of FAs
- LCAD: long-chain-acylCoA-dehydrogenase (for FAs with more than 10 carbons left)
- MCAD: medium-chain (for FAs with 8-10 carbons left)
- SCAD: short-chain (for FAs with less than 8 carbons)
13
Q
MCAD Deficiency
A
- lack of medium-chain acyl-CoA dehydrogenase
- results in fasting hypoglycemia, hypoketosis, C8-C10 acyl carnitines in the blood, dicarboxylic acidemia, vomiting, coma, and death
14
Q
Explain the mechanism for fasting hypoglycemia and hypoketosis, and C8-C10 acyl carnitines in the blood in MCAD deficiency.
A
- fasting leads to lipid mobilization to create ATP from fatty acids, but without MCAD, not enough ATP can be generated from B-oxidation = hypoglycemia
- in the liver, not MCAD means a lack of acetyl-CoA for ketone body synthesis = hypoketosis
- once the FA-CoA’s reach a length of 8-10 carbons, they will not be able to continue to be oxidized and they will build up and eventually spill out into the cytoplasm and then into the blood
15
Q
Explain the mechanism for dicarboxylic acidemia in MCAD deficiency.
A
- the FA back-up in MCAD deficiency will result in FA accumulation in the cytoplasm, where FAs will enter peroxisomes to under omega-oxidation in an attempt to generate any more ATP
- omega-oxidation occurs at the omega carbon (the methyl carbon/last carbon) to generate 1 NADH and a dicarboxylic acid, which is metabolic dead
- dicarboxylic acids eventually build up and spill out into the blood to cause dicarboxylic acidemia (dicarboxylicemia)
