Pan-agonists of PPARs and PGC-1α in Mitochondrial Disease, Autism and Sport

Today’s post should be of interest to those concerned about mitochondrial disease and mTOR.

mTOR is a very important signaling cascade that often dysfunctional in autism. Many aspects of autism and its comorbidities can be traced back to mTOR.

The going is easier with a PPAR pan-agonist 

mTOR integrates the input from upstream pathways, including insulin, growth, and amino acids.   mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of metabolism and physiology, with important roles in the function of tissues including liver, muscle, adipose tissue, and the brain.  It is dysregulated in human diseases, such as diabetes, obesity, certain cancers and indeed autism.

One important process affected by mTOR is the creation of new mitochondria in your cells.  Each cell has many mitochondria, but in some people there are not enough and/or they may not work properly.  

Mitochondrial Disease and Autism

In the above post we saw that Oxidative phosphorylation (or OXPHOS in short) is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy.  This takes place inside mitochondria.

The five enzymes required have simplified names: complex I, complex II, complex III, complex IV, and complex V.

The most common problem in autism is a lack of complex 1, this leads to a lack in the production of energy (ATP) in cells.  In your muscles this will appear as a lack of exercise endurance and in your brain as a lack of cognitive function.

On that rather intimidating chart (below), all about mTOR, tucked away at the bottom right is PGC-1α.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is the master regulator of mitochondrial biogenesis.

PGC-1α may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.

PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a many factors, including:-

·         Exercise  (gradual endurance training)

·         PPARδ , PPARγ and it was thought PPARα

·         AMPK (Metformin, or AICAR)

·         Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Interestingly, massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria. Many autism parents believe in various massage therapies. 

Metformin is a very old drug to treat diabetes, it does activate AMPK but unfortunately it also inhibits the Complex 1 mitochondrial enzyme. This might explain why one reader of this blog found it had a negative effect in her son.  In some types of cancer metformin can be used to “starve” the cancer cells of energy and stop them proliferating.

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

AICAR was thought to have been used by cyclists in the 2009 Tour de France, it is a heart drug from the 1980s. It activates AMPK and increases nitric oxide production from endothelial nitric oxide synthase.

Here is the lower right part enlarged:-

  

The above chart, while complex does not give the complete picture regarding PPAR.

It appears that the type of PPAR that is needed to activate PGC-1α  is actually PPARδ  (PPAR delta). For a long time researchers thought it was PPAR α (PPAR alpha).

PPAR delta, but not PPAR alpha,activates PGC-l alpha gene transcription in muscle

PGC-1 alpha induces mitochondrial biogenesis in muscle and its activity has been related to insulin sensitization. Here, we report that fibrates induce PGC-1 alpha gene expression in muscle both in vivo and in vitro. However, only activation via PPAR delta but not PPAR alpha underlies this effect. PPAR delta induces PGC-1 alpha gene transcription through a PPAR-response element in the PGC-1 alpha promoter. Moreover, PGC-1 alpha coactivates the PPAR delta-responsiveness of its own gene. A further positive autoregulatory loop of control relies on the induction of PPAR6 expression by PGC-1 alpha. These data point to a distinct value of PPARdelta rather than PPAR alpha agonists in the improvement of oxidative metabolism in muscle.

Peroxisome proliferator-activated receptors (PPARs)

There was a post in this blog a long time ago about all the PPARs. There are three types (alpha, delta and gamma) just to confuse us, sometimes delta is called beta.

• α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
• β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin
• γ (gamma) - although transcribed by the same gene, this PPAR through is expressed in three forms:
• γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
• γ2 - expressed mainly in adipose tissue
• γ3 - expressed in macrophages, large intestine, white adipose tissue.

It does seem that activating alpha, gamma and delta has potential benefit.

The PPAR alpha agonist PEA is available as a supplement and as food for medical purposes In Italy and Spain.  It has been proposed for various inflammatory and pain syndromes. A large trial at a Skoda car factory in 1972 showed that PEA was protective against flu and the common cold.

Palmitoylethanolamide:A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold 

Fibrate drugs are PPAR alpha agonist drugs used to lower cholesterol. A key point here is that these drugs also activate other types of PPAR as well.

PPAR gamma agonists are widely used to treat diabetes.  They improve insulin sensitivity and decrease some inflammatory responses. They lower cholesterol.

PPAR delta has various antidiabetic effects and agonism of PPAR delta changes the body's fuel preference from glucose to lipids. Recently it was shown that PPAR delta can be activated to promote biogenesis of mitochondria.

It does appear likely that there is some interaction between the PPARs.

Using the mild PPAR gamma agonist, Sytrinol, which gives a long term cholesterol lowering effect, gives a short term cognitive and behavioral improvement in autism.

Pioglitazone is used to lower glucose levels in type 2 diabetes and is a PPAR gamma agonist.  It has been shown to have a positive effect in autism and more trials are in progress. It also binds to a lesser extent to PPAR alpha.

Our reader Maja is investigating whether Sytrinol will maintain its initial good effect when combined with a mild PPAR alpha agonist, like PEA. 

Pan-agonists of PPAR

Bezafibrate appears to be the best known “pan-agonist” of PPAR alpha, gamma and delta.

The PPARpan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome 

   
Bezafibrate as treatment option in patients with mitochondrial complex I (CI) deficiency

These results support bezafibrate as a promising treatment option for specific subgroups of patients with CI deficiency.

Less well known is the natural substance Berberine. 

Berberine Is a Potent Agonist of Peroxisome Proliferator Activated Receptor Alpha

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

Effect of berberine on PPAR alpha/delta/gamma expression in type 2 diabetic rat retinae.

The multifaceted drug Telmisartan, from a recent post, is also a pan-agonist of PPARs. It is usually quoted as being a PPAR delta agonist. 

Telmisartan increases lipoprotein lipase expression via peroxisome proliferator-activated receptor-alpha in HepG2 cells.

Telmisartan is a promising cardiometabolic sartan due to its unique PPAR-gamma-inducing property

Angiotensin II receptor blockertelmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.

AICAR

The drug AICAR is thought of as an AMPK activator rather than a PPAR agonist, but it does affect all three types of PPAR.

AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression

Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.

Conclusion

It looks like some athletes, seeking an advantage, are already using the above strategies to improve their exercise endurance; having more mitochondria is of course a competitive advantage.  A list of all the substances banned in sport might be another good source of therapies not only for autism, but also dementia.

Since mitochondrial dysfunction is a feature of Parkinson’s, Huntington’s and Alzheimer’s there are some investigations ongoing. There is even a trial to perk up the mitochondria in people with Bipolar using Bezafibrate.

It is odd that Sytrinol has only a short term positive effect in most people with autism, although our reader RG’s daughter has a long term benefit. I suspect some people may need a pan-agonist, there may be some interaction/crosstalk/ feedback that we are not aware of.

It would be nice to have some data on the relative potency of Bezafibrate,  Telmisartan and Berberine across alpha, delta and gamma receptors, otherwise we are left with trial and error.

The advantage of Berberine is that it is an OTC supplement.

AICAR is also interesting.

Metabolic Syndrome & Autism

Today’s post is not just about autism.

Having written 370 posts in this autism blog, I sometimes feel that I am becoming a bit of an expert on diabetes (and COPD), which you might think has nothing to do with autism.

I was talking to a friend of mine who has type 2 diabetes; he was telling me about all the other things that are going wrong with him, because he actually has “metabolic syndrome”.

What exactly is metabolic syndrome?  It really is not a very good name. Sure you can have a metabolic system, but there are going to be many different ones.  It looks like in the world of medicine there is just one.

The common problem is that in late middle age many people get overweight around their waist, they also have increased blood pressure, high blood sugar and abnormal cholesterol, or triglyceride levels. This combination of symptoms is called metabolic syndrome and it increases your risk of heart disease, stroke, diabetes and much more. (see chart above, even high uric acid/gout is there)

The clever way to treat metabolic syndrome would be to treat the underlying molecular biology, rather than each symptom one by one.  This is not as hard as it may sound, just from reading about the biology of autism, I was telling my friend lots of things he could suggest to his doctor.

If you are going to take a drug to lower blood pressure, why not take the one that also protects your beta cells, the ones that produce insulin, from dying? If you are going to take an ACE inhibitor, why not take the one that will also improve your insulin sensitivity. Instead of taking a glitazone drug that is effective at lowering blood glucose, but has not been shown to reduce the long-term complications of diabetes (such as heart disease and stroke), why not take a single drug that does all three?

Metabolic Syndrome & Autism

It is not surprising to me that research shows that parents who develop metabolic syndrome have an increased likelihood of already having children with autism.

Nor is it a surprise that people with autism, or schizophrenia, have themselves a tendency to various kinds of metabolic syndrome; in fact I would suggest that autism is a metabolic syndrome, just not always the same kind.

It is not a surprise that the drugs produced to treat the classic metabolic syndrome seem to provide such a good hunting ground for autism drugs.

We know that glitazone drugs, being PPAR gamma agonists, should help some kinds of autism and also that PPAR delta agonists may help some with mitochondrial disease. The issue I have with glitazone drugs is their safety in long term use.  Another glitazone autism trial is underway in Canada. Glitazone drugs are used to improve insulin sensitivity in type 2 diabetics.

Bezafibrate is getting a well-deserved trial for mitochondrial disease. Through its action on PPAR, where it is a “pan-agonist”, it is thought that Bezafibrate should trigger biogenesis of mitochondria. Bezafibrate is an old drug to lower cholesterol.

One very interesting candidate drug for autism is Telmisartan which will be covered in a coming post on Angiotensin II in the brain.  Telmisartan is an Angiotensin AT1 agonist, which means it will lower blood pressure, but it does numerous other things. It happens also to be a PPAR gamma/delta agonist.  It improves insulin sensitivity and lower blood glucose levels.  It also modifies the immune system by reducing Il-17a, an important inflammatory cytokine found elevated in both autism and schizophrenia. It also reduces leptin release and prevents leptin resistance. Leptin levels are high in autism and leptin resistance is feature of obesity.

One of the drugs often prescribed to people with metabolic syndrome is Atorvastatin, which some readers of this blog have found improves the application of cognitive ability in their case of autism.

If I had metabolic syndrome, after losing weight, I would choose Atorvastatin, Verapamil and Telmisartan as my top three drugs; none of which are prescribed to that friend of mine. I would also add a glass of beetroot juice which is vasodilating; it is not a drug, but should do plenty of good. I would use an antioxidant like ALA (alpha-lipoic acid) and use sulforaphane to activate the body’s antioxidant genes via Nrf2; many side effects of metabolic syndrome are caused/aggravated by oxidative stress.