Concepts
Active hepatic FA beta ox drives ketogenesis (in mito). Synth in liver while its oxidation is extrahepatic. Activated by glucagon.
Principles
Ketones with low pKa so soluble
1 rate limiting step = driven solely by hepatic beta ox
Origin
Source = liver Consumed = all mito but liver Precursor = FA (add CH20 and 6 ketogenic AA's [Leucine and Lysine])
Ketone Synth Points
- 3 Acetyl-CoAs create acidic (pK=3.5) compound for global export
- Mito CoASH retained for reuse
- B-OH-Butyrate dehydrogenase for D-isomers only
- In plasma - spont decarb creates volatile Acetone (also a trans ketone and resp for Diabetes fruit breath)
Ketone Synth Reg
Limiting step = HMG-CoA Synthase (not allo)
Nad/Nadh ratio
Maintained by acetoacetate reduction to B-OH-But via NADH
Ketone synth Draw
On paper
Ketone as fuel users
Muscle, heart, brain, kidney, 10-12 ATPs = Acetyl CoA, liver and RBC excluded, used in fetus
Ketone as fuel path
- B-OH-But enters and oxidized
- Succinyl CoA donates CoA to activate acetoacetate transferase (not in liver)
- B-ketothiolase to 2 Acetyl CoA’s
- 2 Acetyl CoA and 1 OAA to 2 citrate in TCA
Ketone as fuel Draw
On Paper
Ctrl of Ketogenesis
No direct allosteric
Main Factors = Substrate (FA) avail; Induction of HMG CoA synthase (act by fast, fat diet = increased lipid catabolism)
Insulin def leads to increased lipid degradation
