Thursday, 8 March 2018

L-Carnitine, ketolytic enzymes and therapeutic ketogenic diets for cancer management.

L-Carnitine plays an absolutely vital role in the metabolism of fatty acids.

Mo Farah is recently, somewhat controversially been pruported to have had an injection of L-Carnitine before the 2014 London Marathon for performance gains. It is worth noting that Mo Farah is an endurance athlete, so fat is the predominant fuel source. Fat oxidation rate is high so if you can sustain this for a longer period of time you can improve limits of exhaustion.

Carnitine shuttle (1)
This IV administration by Mo Farah is now being seen by the media in this country as 'cheating within the rules' with increased scrutiny recently of 'marginal gains' in athletic performance and sport in general after the cycling 'scandal' with Team Sky riders making the most of Therapeutic Use Exemptions (TUEs) that are known to improve performance for endurance athletes.



What helps athletes often has great potential for cancer patients- ie. infusion of nutrients, certain drugs, nutritional supplements, hyperbaric chambers, cold induced thermogenesis, infrared saunas, etc.

It is interesting....

Like Mo Farah I also take L-Carnitine because it ensures efficient transfer of long-chain fatty acids to mitochondria for subsequent β-oxidation. The brain has an abundance of mitochondria and if you subscribe to the mitochondrial defect theory of cancer as I do its kind of a no brainer (pun intended) that you would want to make the most of everything you can do to do try and restore mitochondrial function here. This can potentially be very beneficial for ensuring that ketone bodies produced during fasting, or fats on the ketogenic diet actually get used so that we can attempt to attain more healthy mitochondria.

This is what I take
There is exhaustive evidence showing how supplementation with L-Carnitine could benefit cancer patients, mostly for reducing general fatigue during chemotherapy (2) but also for normalising lipid metabolism for more general health (3). Anti-dementia effects have been proposed and suggested when co-administering L-Carnitine with medium chain triglycerides (MCTs) and other agents (5, 6). A higher rate of absorption would result in rapid perfusion of the liver, and a potent ketogenic response.


Perhaps an important consideration: 

If you are thinking of taking this as a brain cancer patient however, it may be worth some exploration to see if your tumour has increased activity of ketolytic enzymes to see if it can use fats to proliferate. You can ask about this from histological findings. 

Ketone body ketolytic enzymes to assess expression of include (4): 

Succinyl CoA: 3 Oxoacid CoA Transferase (OXCT1)
3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and BDH2) 
Acetyl-CoA acetyltransferase 1 (ACAT1) 


This can be the case in more aggressive tumours rather than typically lower grade, more solid tumours. I suspect this may be because the tumour is more diffuse, and as such the cell membrane may lack integrity and become more permeable. This is a theory I have based on research looking at alterations of membrane integrity and cellular constituents in neuroblastoma and glioma cells (8). 

I could be completely wrong with that theory, but either way there is often an overexpression of Fatty Acid Synthase (FASN) in high grade gliomas (7), a key lipogenic enzyme in glioma stem cells (GSCs), as well as other important metabolic enzymes, meaning aggressive tumours will try to use whatever they can to grow and thrive and are excellent at adapting to use alternative fuels when you restrict main substrates. These tumours will use glucose, amino acids, fats and nucleic acids for energy, and while the demand will be different for each, as the tumour becomes more aggressive the amounts will change and it becomes more and more resistant to even the most aggressive treatments. 







6. Odle, J., 1997. New insights into the utilization of medium-chain triglycerides by the neonate: observations from a piglet model. The Journal of nutrition127(6), pp.1061-1067.



17 comments:

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  2. Hi Andrew,
    I love your blog! Your determination and persistence to find all the best information is commendable! Just a quick question, I have had surgery for a grade 2 astrocytoma and am facing chemo/radiation. I also have multiple sclerosis. I have been able to maintain a strict keto diet and am considering supplementing with LCarnitine. What dose do you take or suggest I start with for maximum benefit?

    ReplyDelete
    Replies
    1. thank you. Personally I wouldn't have chemotherapy or radiotherapy for a grade 2 astrocytoma, its controversial even for a grade 3 so I'm not sure why your oncologist is keen to do this. Please seek 2nd and 3rd opinions on this before you make any decisions because its a huge thing. Its difficult to determine a therapeutic dose because this can depend on how your current diet is structured as well as your individual circumctances. However I notice that in most studies on cancer patients they will use at least 3,000mg per day of Acetyl-L-Carnitine. This form of carnitine is proposed to be better able to cross the blood brain barrier compared to L-Carnitine and Acetyl-L-Carnitine appears to be the preferred form of Carnitine for brain and nerve support.

      Delete
    2. I didn’t expect that reply! Lol! I have had a second opinion and the suggestion was to delay radiation but opt for temozolomide as a chemo therapy option. The rational for treatment (radiation and chemo) is adding years to my life...why do you suggest I not have chemo or radiation?

      Delete
    3. Sorry Andrew, I was hasty in my reply. What I meant was the rational of treatment was that it has been shown from clinical trials to delay the tumor from coming back by so many years. My oncologist said 3-4 with radiation alone, and 2-3 more with PCV cocktail after. That is, radiation alone delays the tumor coming back 3-4 years longer, than by doing nothing.

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    4. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500925

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  4. Hi Andrew,

    Thank you for your blog and all the research that you kindly share with us.

    I have a concern regarding L-Carnitine and Thyroid, since it is described in many papers as a thyroid hormone suppressant.

    Carnitine may partially block activity of thyroid hormones by inhibiting entry of these hormones into the nucleus of hepatocytes, neurons and fibroblasts. Thyroid hormones interact with lipid metabolism by increasing long chain fatty acid oxidation through activation of carnitine dependant fatty acid import into mitochondria. (Stargrove 2009).

    Benvenga et al proposed L-Carnitine to treat hyperthyroidism.

    We know that thyroid hormones exert a control on oxidative phosphorylation and ATP production. If L-Carnitine improves fatty acid oxidation and thus ATP production, how can that be positive if thyroid hormones are down regulated ?

    Recent research showed that T2 (3,5 diiodothyronine) supplementation, increased significantly complex IV activity and oxygen consumption in hypothyroid rats. Thus Thyroid hormones are also playing a big role in mitochondrial health and probably biogenesis.

    How do we reconcile that apparent paradox where L-Carninitine would be beneficial for the brain thanks to a better OXPHOS of fatty acids and its effects on thyroid hormones and the subsequent down regulation of OXPHOS ?

    Regards

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  8. Hi Andrew,

    Thanks for sharing this information! Curious if you could expand a little more on the "aggressive tumor" piece you concluded with. Are you saying that very aggressive tumors may also learn the "ketogenic approach" and may learn to use fats to keep growing? Was interested to see if you had any research that points to this (if that is what you're saying).

    Thanks for your time!

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