Can Mitochondria Be Healed with Cis-Vaccenic Acid (Through ELOVL5 Activation)?

We will continue exploring cis-vaccenic acid (CVA), which appears to be a very important component of one very special material used in mitochondria, specifically in the inner membrane. Yes, that material is cardiolipin, a unique phospholipid with four connected fatty acid chains. A normal phospholipid contains only three chains, while cardiolipin contains four.

If you have no idea what cis-vaccenic acid is, or if you think you obtain it from milk fat, first read my previous post.

It is usually stated that cardiolipin mainly contains linoleic acid (18:2n-6). However, as I found out, mitochondrial function is strongly influenced by the presence of CVA. In one study, I read that this is related to the composition of cardiolipin. Then AI found me a rather old study examining its exact composition (dating back to 1985), where cis-vaccenic acid is mentioned. And indeed, CVA (18:1n-7) is the second most abundant fatty acid at the 2(2") positions of cardiolipin! The content of oleic acid (18:1n-9) is five times lower than the content of CVA, and for example in rat hearts there is only about twice less of it than linoleic acid. Take a look at the composition.

Depending on the tissue type, the composition differs slightly, but CVA still remains the second most abundant fatty acid. At the second position, it is present in amounts between 15 and 26 percent. Therefore, it must be absolutely indispensable for proper mitochondrial function.

How do we obtain it? It is a product of de novo lipogenesis and is not an essential fatty acid. Our cells can synthesize it themselves. They only need two enzymes for this, SCD1 and ELOVL5. But they also require NADPH molecules as a cofactor.

I would say that a lack of NADPH molecules could be the key issue here. If NADPH molecules are consumed for fat synthesis and storage or for fighting inflammation (activity of NADPH oxidase NOX2), there may be a shortage of NADPH for the elongation of cis-palmitoleic acid (C16:1n-7) into cis-vaccenic acid (18:1n-7). This could then disrupt proper cardiolipin formation and mitochondrial function.

We should therefore be interested in studies examining the activation and deactivation of ELOVL5 and how the activity of this enzyme is modulated. I already showed one study here in the previous post.

Let us look at another paper. It is also older, dating from 2010, and examines the effect of ELOVL5 activation in mice fed either a standard low-fat diet containing 10% fat (D12450B) or a classic experimental high-fat diet (60% fat) based on lard and sugar (D12492).

In an older post I wrote that lard probably does not contain everything necessary for activating proper fat burning. In this study they mention that feeding lard reduces ELOVL5 activity. They therefore created a model in which they additionally increased ELOVL5 activity through genetic modification using an adenovirus. What would be the outcome of such an experiment?

First, let us look at the results of ELOVL5 activation (Ad-Elovl5) on insulin sensitivity and blood glucose levels for the low-fat (Low Fat) and high-fat (High Fat) diets.

We can see that blood glucose levels on the high-fat diet normalized to the same level as on the low-fat diet after ELOVL5 activation. The activation of ELOVL5 occurred only during the final five days of the study, which lasted a total of 12 weeks. The change was therefore practically immediate.

Let us also look at the change in body weight. It is clear that ELOVL5 activation led to a reduction in total body weight, but statistical significance was not achieved; five days is probably too short for sufficient weight loss even in mice.

Liver weight increased after ELOVL5 activation. This is interesting and is apparently related to lower triglyceride export from the liver.

As I already stated in an older post, a diet based purely on lard has certain deficiencies. Something is probably missing in lard, and fat burning is not sufficiently activated. According to the latest findings, this could be precisely due to insufficient restoration of cis-vaccenic acid (C18:1n-7) at the second position of cardiolipin in mitochondria. Its deficiency increases oxidative stress, thereby suppressing fat burning, increasing PUFA peroxidation, and also promoting greater fat storage.

A high-fat diet based on lard significantly limits the production of omega-7 monounsaturated fatty acids. They are almost absent from the diet, and the high presence of oleic acid suppresses the activity of the SCD1 enzyme, i.e. delta-9 desaturase. Even activation of ELOVL5 cannot fully correct this; only the C16:1n-7/C18:1n-7 ratio changed. However, under the low-fat diet there was a significant increase.

Let us also look at how gluconeogenic enzymes dependent on activation of the PPARα factor are affected.

We can see strong suppression of gluconeogenic enzymes here, such as pyruvate carboxylase (Pcx) and G6Pase (G6Pc). This is reflected in lower insulin resistance and lower blood glucose levels on the high-fat diet.


Quote from the study:

"The high-fat diet significantly lowered hepatic 16:1,n-7 and 18:1,n-7 content. Elevated Elovl5 activity significantly increased the relative abundance of 18:1,n-7 in liver of mice fed the low-fat diet (Ad-Luc, 3.9 ± 0.73 mol% and Ad-Elovl5, 5.5 ± 0.72 mol%, P < 0.01, ANOVA) but not in mice fed the high-fat diet. Stearoyl CoA desaturase-1 (SCD1) converts 16:0 to 16:1,n-7; the high-fat lard diet and elevated Elovl5 activity suppressed hepatic SCD1 expression."

End of quote

Did you know that in studies examining obesogenic fats in mouse models, olive oil usually does not perform very well? That is, oleic acid! It gets stored and causes obesity. Why?

Perhaps it is the same problem — a high intake of olive oil suppresses the activity of the SCD1 enzyme and may therefore cause a deficiency of omega-7 palmitoleic acid. Would supplementation with foods high in palmitoleic acid (C16:1n-7) help?

There are not many studies, but for example here the authors examined the effect of palmitoleic acid on the rate of glucose processing in white adipose tissue.

I do not know whether the authors were aware that palmitoleic acid is a substrate for the production of cis-vaccenic acid for mitochondrial cardiolipin, but the results are interesting. Glucose processing was significantly accelerated by palmitoleic acid both in the basal state and during insulin stimulation. This is caused by activation of the AMPK kinase, which phosphorylates for example the ACC enzyme and thus reduces fat storage.

If we wanted to activate both the SCD1 desaturase and the ELOVL5 elongase so that our liver would produce enough omega-7 monounsaturated fatty acids, then supplementing with MCT oil might be suitable. MCT oils activate PPARα as well as various desaturases and elongases, so I would not even be surprised if their mechanism of action were caused precisely by improved cardiolipin quality in mitochondria. We have known for a long time that MCT oils improve carbohydrate metabolism.


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References:

Positional distribution of fatty acids in cardiolipin of mitochondria from 21-day-old rats

Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese BL/6J mice

Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity

Palmitoleic acid (n-7) increases white adipocytes GLUT4 content and glucose uptake in association with AMPK activation





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