Ketones and Autism Part 6 - Capric Acid (C10) for Mitochondrial Disease, in Particular Complex 1, plus more on Metformin

Capric Acid (C10) is so named because it smells like a goat (Goat in Latin = Caper)

Photographer: Armin Kübelbeck, CC-BY-SA, Wikimedia Commons

Rather than Goaty acid, C10 is called Capric acid, or indeed Decanoic acid (after its 10 carbon atoms). Today’s post is indirectly again about ketones, because if you eat a Ketogenic Diet (KD) you are likely to consume a fair amount of Capric acid (C10).

I have written a lot in this blog about mitochondria, even though I do not think my son has mitochondrial dysfunction. Clearly many people with autism do have a lack of one or more of the critical mitochondrial enzyme complexes that allow glucose to be converted to ATP (usable energy), by the clever process OXPHOS (Oxidative phosphorylation).

The “rate limiting” enzyme is usually Complex 1, meaning that is the one it is most important not to be short of.

Another favourite, but obscure, subject of this blog is PPAR gamma.

Peroxisome proliferator-activated receptors (PPARs) are a group of proteins that function as transcription factors regulating the expression of certain genes. Transcription factors are particularly important because they trigger numerous effects.

PPAR gamma plays a key role in fat storage and glucose metabolism, but has other functions. 

Activation of PPAR-gamma by Capric acid (C10) has been shown to increase the number of mitochondria, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase. 

So, if you have autism and impaired mitochondrial function, C10 may well give a benefit because it can increase the peak power available to your brain.

The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells

The Ketogenic diet (KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line (SH-SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.

Capric Acid (C10) as a PPARγ agonist

As shown in the above study the mechanism by which C10 benefits the mitochondria is via PPARγ agonism.

Here is another study confirming that C10 is indeed a PPARγ agonist.

Identification and Mechanism of 10-Carbon Fatty Acid as Modulating Ligand of Peroxisome Proliferator-activated Receptors

Background: Mechanism of action of medium chain fatty acid remains unknown.

Results: Our results show that decanoic acid (C10) binds and activates PPARγ.

Conclusion: Decanoic acid acts as a modulator of PPARγ and reduces blood glucose levels with no weight gain.

Significance: This study could lead to design of better type 2 diabetes drugs.

Other PPARγ agonists

PPARγ agonists have been covered previously in this blog and we know that glitazones, a class of drugs for diabetes, do improve some types of autism. Glitazones are PPARγ agonists.

Metformin, a very widely used drug for type 2 diabetes, works differently to Glitazones, but I did suggest a while back it should help some types of autism. Last year it was indeed found to be beneficial in Fragile X.

Diabetes drug may help symptoms of autism-associated condition

 "Basically, it's something like a wonder drug," Sonenberg said.

The study suggests that metformin might also be used to treat other autism spectrum disorders, said Ilse Gantois, a research associate in Sonenberg's lab at McGill.

"We mostly looked at the autistic form of behaviour in the Fragile X mouse model," explained Gantois, who is co-lead author with McGill researchers Arkady Khoutorsky and Jelena Popic. "We want to start testing other mouse models to see if the drug could also have benefits for other types of autism."

Metformin is very cheap and has been used in humans for 60 years. It is another example of re-purposing a drug from Grandpa’s medicine cabinet to treat Grandson’s autism. 

Metformin has been trialled to combat obesity in idiopathic autism caused by antipsychotics. It did help with weight gain, but no comments were made about behavioural improvements, but then those studied were on antipsychotic drugs, which might mask such effects. 

Glitazone-type drugs appear more problematic than Metformin.

There are natural PPAR gamma agonists and they are often used to lower cholesterol, lower blood sugar and improve insulin sensitivity.

Sytrinol, a product containing flavanols tangeretin and nobiletin does indeed have a positive effect on some people’s autism, but for most people (but not all) the effect is lost after a few days.

Our doctor reader Maja, did suggest combining it with a PPARα agonist to see if the effect might be maintained.

This combination has indeed been researched for type 2 diabetes.               

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.

There actually is another natural substance that is an agonist of both PPARγ and PPARα, Berberine, the alkaloid long used in Chinese medicine.

In the research it is suggested that “BRB localizes in mitochondria, inhibits respiratory electron chain and activates AMPK”, which is not what you would want. But this may not be correct.

People who like supplements might want to follow up on Berberine.

Berberine is used by many people with diabetes and a few with autism, for all kinds of reasons, from mercury to GI problems.

Berberine is a potent agonist of peroxisome proliferator activated receptor alpha.

Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.

Berberine activates peroxisome proliferator-activated receptor gamma to increase atherosclerotic plaque stability in Apoe^-/- mice with hyperhomocysteinemia.

                                                                                                                                     

Sources of Capric Acid (C10)

Goat milk is a good source of capric acid.

Capric acid is 8-10% of coconut oil and 4% of palm kernel oil

Capric acid is a large component (about 40%) of the less expensive MCT oil supplements.

http://cdn.intechopen.com/pdfs/39464/InTech-The_effect_of_fatty_acids_in_goat_milk_on_health.pdf

1.2. Fatty acid composition in goat milk fat Average goat milk fat differs in contents of its fatty acids significantly from average cow milk fat, being much higher in butyric (C4:0), caproic (C6:0), caprylic (C8:0), capric (C10:0), lauric (C12:0), myristic (C14:0), palmitic (C16:0), linoleic (C18:2), but lower in stearic (C18:0), and oleic acid (C18:1) (Table 1). Three of the medium chain fatty acids (caproic, caprylic, and capric) have actually been named after goats, due to their predominance in goat milk. They contribute to 15% of the total fatty acid content in goat milk in comparison to 5% in cow milk (Haenlein, 1993). The presence of relatively high levels of medium chain fatty acids (C6:0 to C10:0) in goat milk fat could be responsible for its inferior flavour (Skjevdal, 1979). 

             

Conclusion

If someone responds well to coconut oil or cheaper MCT oil the reason may have more to do with PPAR gamma and improved mitochondrial function than anything to do with ketones and what they do.

Cheaper MCT oils are mainly a mixture of C8 and C10. To maximize the production of the ketone BHB you really want just C8, but if what you really need is a PPAR gamma agonist, to perk up your mitochondria, it is the C10 you need.

You may indeed benefit from both ketones and agonizing PPAR gamma, in which case you either follow the Ketogenic Diet, or supplement BHB, C8 and C10.

I think this explains why some people with autism reportedly respond well to teaspoon-sized doses of cheaper MCT oil or small amounts of coconut oil.

If you have Complex 1 mitochondrial dysfunction then a dose of Capric acid (C10) is likely to help.

Berberine may, or may not be, as effective as C10. I doubt we will ever know. I think C10 is the better option. 

I wonder when the Canadian researchers will publish their results showing whether Metformin is beneficial beyond Fragile X syndrome. They do not really know why it helps, but that is a repeating theme in medicine.  It is a cheap safe drug, so it would be a pity to waste time finding out if it could be repurposed for some autism.