How Exactly Do Seed Oils Deactivate Cellular Energy Deficiency Signaling?

One of the main sensors of energy sufficiency in the cell, that is, a sufficient supply of ATP molecules, is the enzyme AMPK. It is activated whenever the amount of AMP molecules increases. But does it really work "every time"? An adequate energy supply for all cellular functions is so fundamental that we should ask whether certain substances can suppress this signaling. The cell then suffers from an energy deficit and enters various energy-conserving states, for example pseudohypoxia or cellular senescence, which is characterized by fermentative metabolism to reduce the production of reactive oxygen species (ROS, such as hydrogen peroxide), but also by the shutdown of processes that repair damaged DNA (which is a common occurrence caused, for example, by UV radiation or ionizing radiation).

So, do we know of any substances that block AMPK activity? Yes, we certainly do. One is the well-known autooxidation product of the omega-6 fatty acid linoleic acid, a molecule called 4-hydroxy-2-nonenal (HNE). It does not act directly, but through the kinase LKB1, to which HNE "binds." The LKB1 kinase phosphorylates, and thereby activates, the AMPK enzyme (P-AMPK). Only a properly phosphorylated enzyme is fully functional. Blocking LKB1 renders the AMPK enzyme nonfunctional and disrupts the signaling of ATP deficiency. Among other functions, activated AMPK also phosphorylates the ACC enzyme (P-ACC), thereby inhibiting it and preventing the production of malonyl-CoA molecules.

If the LKB1 enzyme is blocked by HNE molecules, then AMPK is not sufficiently activated either, and the ACC enzyme will not be phosphorylated. This leads to the initiation of de novo lipogenesis, and the resulting malonyl-CoA molecules prevent fat oxidation by simply blocking fatty acids from entering the mitochondria. Fat will therefore have to be stored in greater amounts than necessary. Yes, this is how defective signaling forces the storage of fats circulating in the bloodstream from food, as well as newly synthesized fat produced in the liver.

All of this can be found in an interesting study published as early as 2008. So this is not new information. Almost nobody is simply aware of it.

Another study on a similar topic also describes the relationship between HNE, LKB1, AMPK, mTORC1, and the synthesis of new proteins, particularly in connection with cardiac muscle hypertrophy. I have previously discussed the relationship between linoleic acid and pulmonary hypertension caused by the thickening of blood vessels; this study simply provides additional, more detailed information about the mechanisms by which this occurs in the body.

Here we also see that Rapamycin blocks some of the effects of HNE, but don't get too excited. It most likely cannot suppress all of HNE's effects, nor can it help eliminate HNE if large amounts are present.

Many scientists are searching for methods to suppress excessive mTOR signaling. Yet excessive activation of this pathway is clearly observed following stimulation by HNE, the autooxidation product of linoleic acid. Large stores of linoleic acid resulting from unrestricted consumption of vegetable seed oils create a reservoir of flammable material within the body that, once activated by oxidative stress, ignites the production of HNE and subsequently triggers a wide range of metabolic problems.

The solution to these fundamental metabolic problems appears to be very simple—ensure that the cell is exposed to as little HNE as possible. This means promoting its safe removal while also consuming as few foods as possible that either contain HNE or generate it through autooxidation. It may really be that simple. Don't believe it?


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References:

Resveratrol Prevents the Prohypertrophic Effects of Oxidative Stress on LKB1

The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis in cardiac myocytes via activated mTORC1–p70S6K–RPS6 signaling



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