Topic 14: Lipolysis and FA Oxidation Flashcards
Where does DIETARY fat go first upon absorption?
General Circulation, bypassing Hepatic Portal via lymphatic circulation
Where do ketones come from?
Processing of FFAs in the liver
What happens to the glycerol upon lipolysis?
Glycerol via Glycerol Kinase –> G-3-P via G-3-PDH –> DHAP
DHAP can go to Gluconeogenesis (most likely since breaking down fats means you need energy)
OR
directly to the glycolytic pathway
What is Step 1 of FA Beta-Oxidation?
it must be ACTIVATED first with CoA via Acyl-CoA Synthetase
This was also seen in the enterocyte for reassembly of TAGs.
NOTE: ATP is used to generate pyrophosphate and POWER this irreversible reaction. (2 ATP Equivalents)
What is Step 2 of FA Beta-Oxidation?
Fatty Acyl-CoA is combined with CARNITINE via CPT-1 to form AcylCarnitine + free CoA.SH
What is Step 3 of FA Beta-Oxidation?
Acylcarnitine is exchanged for Carnitine via CAT (Carnitine Acylcarnitine Translocase) to enter the matrix
What is Step 4 of FA Beta-Oxidation?
Acylcarnitine via CPT-2 has CoA added and Carnitine removed –> Fatty Acyl-CoA + Carnitine
Note: Reverse action of CPT-1 in cytosol
Are there two separate, distinct pools of CoA in the cytosol and matrix?
Yup. They never cross the IMM and are two separate pools.
What is Step 5 of FA Beta-Oxidation? (Fatty Acyl-CoA has just entered mitochondria)
Fatty Acyl-CoA via Acyl-CoA Dehydrogenase –> Enoyl CoA
Generates FADH2
What is Step 6 of FA Beta-Oxidation?
Enoyl CoA via Crotonase has H2O added to beta carbon –> Beta-Hydroxy-Acyl-CoA
What is Step 7 of FA Beta-Oxidation?
Beta-OH-Acyl-CoA via a different Acyl-CoADH oxidizes to –> Beta-KetoAcyl CoA
Generates NADH
What is Step 8 of FA Beta-Oxidation?
beta-ketoAcyl CoA via Thiolase adds another CoA –> Acetyl CoA!! + Shorter Chain Fatty Acid (which goes back to the top, rinse and repeat)
Generates Acetyl CoA!
How many carbons are removed per each cycle through beta-oxidation?
2 carbons at a time
What is the exception to the beta-oxidation with regard to different length fatty acids?
Different Dehydrogenase enzyme to deal with the various lengths of FAs.
MCFA and SCFA can enter the mitochondria without needing to be activated in the cytosol first.
What is the effect of a double bond (unsaturation) on FA metabolism?
less 1.5 ATP – minimal effect
This is because the step making FADH2 is skipped.
How many ATP are generated from 16C Saturated FA?
7 C-C Cycles (last cycle yields 2 acetyl-CoA) 7FADH2 (*1.5)= 10.5 ATP 7 NADH (*2.5) = 17.5 ATP 8 Acetyl CoA (*10) = 80 ATP FA Activation = -2 ATP Total = 106 ATP
Don’t forget the cost for activation and that the last cycle will yield two Acetyl CoA.
How many ATP are generate from 16:2C unsaturated FA?
So 2 double bonds, all we have to do is skip the first step which is what yields FADH2.
7 C-C Cycles 5 FADH2 (*1.5) = 7.5 ATP 7 NADH (*2.5) = 17.5 ATP 8 Acetyl CoA (*10) = 80 ATP FA Activation = -2 ATP Total = 103 ATP
Again, don’t forget to count the cost of -2 ATP for activation.
Why do ketones result from Beta-Oxidation?
Beta-Oxidation generates a plethora of Acetyl CoA, of which the liver only needed some. Backup causes them to go to the ketone pathway.
What tissues can generate ketones?
mostly the Liver, but also the kidney
What tissues can use Ketones as fuel?
Brain, Heart, Skeletal muscle
What are the ketone bodies we talked about?
1) Acetoacetate
2) Acetone
3) Beta-Hydroxybutyrate (not strictly a ketone but whatevs)
When would we see high levels of ketone bodies in the blood/urine?
Starvation!!
also, uncontrolled Diabetes mellitus – just like being starved all the time
Glucagon levels are UP UP UP - lipolysis increases
Where do excess Acetyl-CoAs in the cytosol go to?
Cholesterol Synthesis
Where do excess Acetyl CoAs in the mitochondria go?
ketone synthesis
What is Step 1 of Ketone formation?
Acetyl-CoA + Acetyl-CoA via Acetyl-CoA Transferase –> Acetoacetyl-CoA plus free CoA
What is Step 2 of Ketone formation?
Acetoacetyl-CoA + Acetyl-CoA via HMG-CoA Synthase –> Hydroxymethylglutaryl-CoA plus free CoA
What is Step 3 of Ketone formation?
HMG-CoA via HMG-CoA Lyase removes Acetyl-CoA –> Acetoacetate!! BOOM ketone!
Is there a Step after Acetoacetate formation?
Of course. Acetoacetate is converted to and back from Beta-Hydroxybutyrate based on the the concentrations of the two.
Also Acetoacetate spontaneously and irreversibly to degrades to CO2 and Acetone!!
How can you tell an animal is ketotic without running bloodwork?
Smell their breath –> ACETONE!
Fruity or Flowery smell (I think it smells like gasoline)
What is Peroxisomal Beta-Oxidation used for?
VLFCA - VERY Long Chain Fatty Acids
Broken down in similar fashion (2 C at a time) until short enough and dumped to cytosol for normal FA Beta-oxidation
What are the end products of VLCFA Beta-Oxidation?
Acetyl CoA and MCFA (octanoic acid)
When is peroxisomal beta-oxidation utilized?
Fasting, High-fat feedings, Thermoregulation (hibernators)
Pretty much when Fat is the ONLY energy source being used.
How is Beta-Oxidation regulated?
CPT-1 is INHIBITED by Malonyl CoA (1st step of building fats)
HSL STIMULATED by: Glucagon, Epi, NorE, Thyroxine, ACTH, TSH, GH
HSL INHIBITED by: Insulin and Ketones
What did Dr. Eng hint would be on the exam?
How to calculate ATP Yield from various length fatty acids.
Regulation of of Beta-oxidation via CPT-1 and HSL.
What’s the advantage of brain and muscle being able to utilize ketone bodies for fuel?
Immediate fuel for the TCA Cycle (ketones can be directly broken down into 2 acetyl CoAs)
Reduces Acidic content of blood (ketones are acids)
What enzyme do statins target to inhibit cholesterol synthesis?
HMG-CoA Reductase
