UA-45667900-1
Showing posts with label PPARγ. Show all posts
Showing posts with label PPARγ. Show all posts

Wednesday, 10 October 2018

Ketone Therapy in Autism (Summary of Parts 1-6)




Open the above file via Google Drive, so it is big enough to read. Click the link below. You can also take links from it to the relevant blog post.

https://drive.google.com/file/d/1Jl_JMUrX7suXz0n_yJPCLPinrvdddBhI/view?usp=sharing

In the mini series of posts on ketones and autism we have come across a long list of effects that will benefit certain groups of people.



1.     Change in gut Bacteria


2.     Ketones as a brain fuel    


3.     Niacin Receptor HCA2/ GPR109A

4.     NAD sparing

5.     CtBP Activation by reducing NADH/NAD+ ratio

6.     NLRP3 Inflammasome inhibition

7.     Class 1 HDAC inhibition

8.     Increase BDNF

9.     Ramification of Microglia

10.PKA activation

11.PPAR gamma activation
It was interesting that the beneficial effect of the Ketogenic Diet in epilepsy is driven by changes the high fat diet makes to the bacteria in your gut and seems to have nothing really to do with ketones. Well it took a hundred years to figure that one out.
In the case of Alzheimer’s, you can see that more than one effect is potentially beneficial. People with Alzheimer’s do have low glucose uptake to the brain, but they also have elevated inflammatory cytokine IL-1B.
In Huntington’s it is the HDAC inhibition effect that seems to be what helps.  This brings us back to HDAC inhibition as a potentially transformative therapy with long lasting effects. It appears that the small number of people who achieve long lasting benefit from short term use of sulforaphane or EGCG may have experienced HDAC inhibition changing the expression of up to 200 genes.  In the case of sulforaphane from broccoli, some people have gut bacteria that produces large amounts of the enzyme myrosinase, which means they convert very much more of the glucoraphanin in broccoli to sulforaphane (an HDAC inhibitor).
It does look like a low dose of a potent HDAC inhibiting cancer drug is what is needed by certain single gene autisms and perhaps some idiopathic autism. This was covered in a dedicated post where we saw the long-lasting benefit of short-term use of Romidepsin. Vorinostat, a very similar drug, but which is taken orally, should be trialled in Shank 3, Pitt Hopkins and Kabuki, to see if the same transformative long-lasting effect can be reproduced.
In Multiple Sclerosis (MS) the effect on Niacin receptor HCA2/GPR109A should help a lot, but so should PKA activation.
In mitochondrial disease it was suggested that increased ketosis will help conserve NAD, which may be deficient. Also, using ketones as an alternative brain fuel may bypass problems that occur when glucose is supposed to be the fuel and thereby boost brain function. The most important effect is likely to be activation of PPAR gamma by C10, which increases the number of mitochondria and boosts the enzyme complex 1.
Many of the people with autism and an overactive immune system stand to benefit from activating CtBP, inhibiting the NLRP3 inflammasome, or activating HCA2/GPR109A.
I think there should be clinical trials using a potent HCA2 activator in autism comorbid with immune over-activation. 
We can see that some people who respond to BHB, experience an immune rebound on cessation, so this helps narrow down the likely beneficial mode of action.  In this immune sub-group, the idea to using other activators of HCA2/GPR109A would seem worthwhile. 

PPAR gamma activation should help those with mitochondrial dysfunction, but this effect is produced only by C10, not BHB or C8. For C10 you eat a ketogenic diet or add it as a supplement (e.g. cheaper MCT oil, or coconut oil).

As recently highlighted by our reader Agnieszka, perhaps the fever effect in autism can be explained by short-term ketosis. Fever is known to sometimes raise the level of ketones, particularly in children (it is called non-diabetic ketosis).  So if your child's autism improves during, or just after fever, test the level of ketones in their urine.


Conclusion

We may have shown the benefits of a high fat ketogenic diet, but there are very many different fats and they do not all produce the same effects.

There are many saturated fatty acids, they are numbered based on how many Carbon atoms they have.

So, C8, known as Caprylic acid has the formula  C8H16O2

Eating C8 looks to be a great way to increase the level of ketones in your blood.

Eating C10 should be good for people with mitochondrial dysfunction and people with diabetes.

Your food contains many other saturated fatty acids and your gut bacteria produce even more.


Common Name Systematic Name Structural Formula Lipid Numbers
Propionic acid Propanoic acid CH3CH2COOH C3:0
Butyric acid Butanoic acid CH3(CH2)2COOH C4:0
Valeric acid Pentanoic acid CH3(CH2)3COOH C5:0
Caproic acid Hexanoic acid CH3(CH2)4COOH C6:0
Enanthic acid Heptanoic acid CH3(CH2)5COOH C7:0
Caprylic acid Octanoic acid CH3(CH2)6COOH C8:0
Pelargonic acid Nonanoic acid CH3(CH2)7COOH C9:0
Capric acid Decanoic acid CH3(CH2)8COOH C10:0
Undecylic acid Undecanoic acid CH3(CH2)9COOH C11:0
Lauric acid Dodecanoic acid CH3(CH2)10COOH C12:0
Tridecylic acid Tridecanoic acid CH3(CH2)11COOH C13:0
Myristic acid Tetradecanoic acid CH3(CH2)12COOH C14:0
Pentadecylic acid Pentadecanoic acid CH3(CH2)13COOH C15:0
Palmitic acid Hexadecanoic acid CH3(CH2)14COOH C16:0
Margaric acid Heptadecanoic acid CH3(CH2)15COOH C17:0
Stearic acid Octadecanoic acid CH3(CH2)16COOH C18:0
Nonadecylic acid Nonadecanoic acid CH3(CH2)17COOH C19:0
Arachidic acid Eicosanoic acid CH3(CH2)18COOH C20:0

C4, familiar as Butyric acid, helps maintain the integrity of the intestinal barrier and the blood brain barrier.  Butyric acid, or butyrate, is also an HDAC inhibitor and it seems that in animal models, and some humans, a small amount can be beneficial but large amounts can have a negative effect. A small amount in humans seems to be about 500 mg a day.  There are earlier posts is this blog on butyrate.

C3, familiar as Propionic acid, is bad for you and too much propionic acid will by itself cause autistic behaviours. NAC counters the effect of propionic acid in mouse models.

All those people eating coconut oil are consuming a 99% mixture of fatty acids with 1% phytosterols.

Phytosterols like β-SitosterolStigmasterolAvenasterol and Campesterol likely explain why coconut oil actually reduces "bad" cholesterol, rather than increasing it, as predicted by the American Heart Association and others. This counters the negative effect of the Palmitic acid (C16).

Lauric acid (C12) is thought to increase HDL ("good") cholesterol and may have a beneficial effect on acne.

Myristic acid (C14) is also thought to increase HDL ("good") cholesterol.

Palmitic acid (C16) raises LDL ("bad") cholesterol and large amounts have other negative effects.

Oleic acid is also found in olive oil and is seen as a fat with beneficial effects.



Fatty acid content of coconut oil
Type of fatty acid pct
Caprylic saturated C8
7%
Decanoic saturated C10
8%
Lauric saturated C12
48%
Myristic saturated C14
16%
Palmitic saturated C16
9.5%
Oleic monounsaturated C18:1
6.5%
Other
5%
black: Saturated; grey: Monounsaturated; blue: Polyunsaturated


So the only "bad" part of coconut oil is the Palmitic acid (C16).

As for MCT oil, what is in that?


In pharmaceutical MCT oil, like the one sold by Nestle, the contents are:-


Shorter than C8      1%
C8 (Octanoic)      54%
C10 (Decanoic)   41%
Longer than C10    4%

What is the effect of those fatty acids with more than 10 carbon atoms?  Nobody likely knows.



Cooking with MCT Oil? 

This is what Nestle has in mind for dinner.


Mct Spaghetti With Meat Sauce






4 Tbsp. MCT Oil® (Medium Chain Triglycerides)
1 lb. very lean ground veal or beef
1 tsp. salt
1/2 tsp. pepper
1/4 cup chopped onion
3 Tbsp. chopped green pepper
1 cup MCT Tomato Sauce (see recipe on site)
2 cups cooked spaghetti

Heat MCT Oil; add veal, salt and pepper.
Cook until meat is brown.
Add onion, green pepper, and tomato sauce. Cook for 30 minutes over low heat.
Add cooked spaghetti, stir and serve.