Dave Asprey has a very interesting extended discussion with Dr Veech on his Bulletproof website, mostly about ketones but also about the history of biochemistry and a number of other subjects. Dr Veech is very pro ketones while being surprisingly anti high fat diets, an interesting combination and clearly far from my own perspective. Much of the interview is simply fascinating in its own right but I'd just like to talk about the aspects with which I disagree. As one must.
Exclusive: Interview with Ketone Expert Dr. Richard Veech
The section of interest is around one hour five minutes in to the discussion. For those who would like some flavour of Dr Veech's uncomfortable stances on a fat based diet, cardiologists and cholesterol you can grind your teeth through the ten minutes leading up to that point. It's pretty obvious that Dr Veech has a lot of reading to do on cholesterol and cardiovascular health, should he so wish.
I had to correct a few relatively minor typos, nothing to do with what was said, just how it got written down, so I've put up the original text followed by my edited version. I've listened to this section three times now and I think my modified transcript is correct:
Original:
Dr. Veech: However, when you’re burning fat, you’re going through beta-oxidation. One reducing equivalent goes to NAD and one goes to
Tidied up:
Dr. Veech: However, when you’re burning fat, you’re going through beta-oxidation. One reducing equivalent goes to NAD and one goes to flavo protein. You’ve already lost 1/3 of your ATP in that step. Go back to your Lehninger, beta-oxidation, you do one NADH, you do one flavo protein. You do that to keep from blowing the mitochondria up.
I sold my copy of the biblical Lehninger at the end of my second year at vet school when we finished biochemistry as a subject in its own right. I have to say I really enjoyed the book. I also midnight question-spotted the urea cycle for my biochemistry written exam and it came up. Yeaha!
Sooooooo. Yes, beta oxidation (of saturated fats) does indeed yield one FADH2 which is embedded in a flavoprotein as well as generating an NADH. Electron transporting flavoprotein (ETF), which docks with ETF dehydrogenase, reduces the CoQ couple and omits pumping the four protons which could have been pumped had a second NADH been generated instead. My back-of-an-envelope calculations suggest an NADH could have been generated instead of the FADH2. This does indeed waste a four protons worth of the ATP which might have been generated.
And yes, the FADH2 is generated to stop damage to our mitochondria. So fats are bad?
With some slight discomfort I have to re-cite (yet again) the Protons thread. The whole point of generating inputs which reduce the CoQ couple is to drive reverse electron flow through complex I. Low levels to trigger insulin signalling, high levels to resist insulin signalling. H2O2 is the second messenger.
The waste of proton pumping by supplying FADH2 at the CoQ couple is offset by it being used to regulate the system. This applies to mitochondrial glycerol-3-phosphate dehydrogenase, driven by glycolysis, or ETFdh driven by beta oxidation of saturated fats. Both initially assist insulin signalling and, as substrate throughput increases, they facilitate resistance to the signal from insulin to accept more calories.
Another sooooooo. FADH2 is, I agree, wasteful but more importantly it also drives reverse electron flow through complex I. And undoubtedly you can have too much of a good thing. Waaaay back in the early Protons posts I spent a lot of time looking at FADH2:NADH ratios and decided that somewhere around palmitic or stearic acids there was a maximum healthy FADH2:NADH ratio, somewhere around 0.48. At that time Dr Speijer was kind enough to supply his paper looking at the development of the peroxisome in LECA, the Last Eukaryote Common Ancestor (not to be confused with LUCA, of the hydrothermal vents).
One major function of peroxisomes is to deal with very long chain fatty acids using a beta oxidation version which does not generate FADH2. Problem solved, no need to blow a gasket in our mitochondria. In fact the peroxisomes shorten VLC fatty acids to octanoate, much beloved of Dave Asprey and Dr Veech.
Minor aside: How might you explode your mitochondria if Dr Veech's concerns were correct re FFAs and his idea about FADH2 being used to reduce the supply of pumped protons from complex I? There is a technique to completely flood your mitochondria with NADH. It's called beta-hydroxybutyrate, particularly if supplied in large amounts from ketone esters. This enters the mitochondria using the monocarboxylate transporters, generates NADH as it converts to acetoacetate then goes on to generate three more NADHs from each of the two acetyl-CoA entering the TCA. These NADHs are potentially capable of pumping membrane popping numbers of protons through complex I, without concerning Dr Veech. And without actually doing any damage, that I can tell. End aside.
Next minor aside: Free fatty acids are not going to explode your mitochondria: Under ketogenic high fat eating there is a combination of elevated free fatty acids (happy happy), low insulin (so no loss of FFAs through insulin induced triglyceride formation), plenty of ATP in the mitochondria to allow uncoupling proteins to function (UCPs must have generous ATP on their mitochondrial matrix end to allow them to function) and those ad lib FFAs are necessary and available to actually carry the protons through the uncoupling proteins. FFAs are essential for uncoupling, no FFAs = no uncoupling, pax mtG3Pdh. FFAs = uncoupling = no exploding mitochondria. End second aside.
I'm left here with my view of a healthy metabolism as one based around beta oxidation of saturated fatty acids. Ketones as they happen, no stress. Nothing originating from the discussion has budged my entrenched position in the least, interesting though it has been to listen to.
Peter
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