On the Harmfulness of Saturated Fats

Yes, everyone knows that, after all, saturated fats are harmful! Don’t eat them! Just look at the following image.

Here we see how liver cells respond to specific free fatty acids, for example to the saturated palmitic acid (PA). We can see that palmitic acid alone produces almost no ATP, allows a large amount of calcium into the cell, causes an excess of reactive oxygen species (ROS), and triggers insulin resistance by reducing phosphorylation of the signaling molecule AKT (pAKT). The conclusion: do not eat saturated fats! It’s completely obvious. Or is it?

Well, let’s continue with the same image. We also have the monounsaturated oleic acid (OA) and the polyunsaturated EPA (for example from fish oil). Then there are the combinations PA+OA and PA+EPA. And we see that PA in combination with a certain amount of unsaturated fatty acids does nothing fundamentally harmful. Why?

I will use another study to show you how fat transport into the cell is probably related to the shape of unsaturated fatty acid molecules. Look at the following image showing how specific free fatty acids translocate CD36 molecules, which help transport long-chain fats across the cell membrane. Long-chain polyunsaturated omega-3 fatty acids DHA and EPA reduce the transport of fats into the cell, probably of all fats, thus preventing the liver cell from being flooded with palmitic acid. Also note the dependence on insulin—high insulin levels help transport fats into the cell, which may not always be beneficial. DHA and EPA help even in the case of high insulin levels to slow the transfer of fats (including saturated ones) into the cell through CD36 translocation.

However, oleic acid does not help in this way; it does not block fat entry and must function through a different mechanism. Which one? In a previous post I stated that oleic acid activates the storage of fats into triglycerides. This also requires higher glucose levels, fructose, or rather activated gluconeogenesis and de novo lipogenesis triggered by oxidative stress (H2O2). Palmitic acid is then elongated and desaturated into oleic acid. This takes some time, so in vitro test results (that is, in a test tube) may differ depending on how much time researchers allowed palmitic acid to transform into oleic acid. In the presence of oleic acid, the transformation of palmitic acid into oleic acid probably occurs more easily, thanks to a more active SCD1 enzyme.

And in the following study on the mechanism of triggering gluconeogenesis by linoleic acid we see that linoleic acid (LA), oleic acid (OA), and palmitic acid (PA) behave the same way. Here, the transformation of PA into OA was evidently activated. But medium-chain caproic acid (CA, C6:0) cannot be desaturated and therefore behaves differently.

I do not have it completely clear yet, but it seems that both gluconeogenesis and lipogenesis are switched on by the same molecules, the same transcription factors, the same mechanism. Specifically through the transcription factors PPAR-α and PPAR-δ.

“... stimulated peroxisome proliferator-activated receptor (PPAR) expression, and MK-886 (PPAR-α antagonist) and GW-9662 (PPAR-δ antagonist) inhibited glucose-6-phosphatase and phosphoenolpyruvate carboxykinase.”

Interpretation:

Stimulation of PPAR-α activated gluconeogenesis (the enzymes G6Pase and PEPCK), and PPAR-α blockers stopped gluconeogenesis.

Doesn’t the PPAR-α molecule also activate fat production? De novo lipogenesis (DNL)? I think so. Fenofibrate and L-165041 are activators of PPAR-α and PPAR-δ. They activate fat metabolism in peroxisomes and the increased level of H2O2 apparently then switches on fat production and storage. Possibly even without fructose and the polyol pathway, simply by activating peroxisomes. The fact that they can also activate gluconeogenesis may be related to increased levels of acetyl-CoA molecules, which activate the enzyme pyruvate carboxylase (PC) and increase the formation of oxaloacetate. That is the main activator of gluconeogenesis. Fat burning in peroxisomes also requires malate and oxaloacetate to transfer energy via NADH, substrates for glucose production. This is due to the impermeability of membranes to NADH molecules. Molecular shuttles must be used to transport molecules from the peroxisome through transporters. So is the activation of gluconeogenesis related to the activation of peroxisomal fat burning? I think so.

The entire chain of triggering gluconeogenesis by fatty acids looks like this

You can see that the whole system begins with detection of a fatty acid by the GPR40 (FFAR1) receptor. As artificial intelligence tells me, GPR40 is quite promiscuous and responds to almost all fatty acids from C8 to C24, but probably most strongly to polyunsaturated fatty acids. We have seen that medium-chain fatty acids do not trigger gluconeogenesis. Saturated fats, probably without a small amount of polyunsaturated fats, may allow calcium into the cell but do not trigger subsequent reactions, do not activate peroxisomes, and the whole system stalls. But if the desaturating enzyme SCD1 is active, nothing bad happens—PA is converted into OA, and peroxisomes are activated normally, and along with that gluconeogenesis and lipogenesis are activated together with desaturation.

Doesn’t it seem strange to you that gluconeogenesis and lipogenesis are so important and necessary for proper fat processing that it seems to me that insufficient activation might be the main problem of poor fat burning? I have already expressed such a hypothesis once while examining the effect of amino acids. And I can add that the body probably knows very well why during fasting it activates the so-called omega oxidation of fats, in which it creates dicarboxylic acids from saturated fats, which are metabolized precisely in peroxisomes, produce H2O2, and thus activate gluconeogenesis as well as the transformation of saturated and polyunsaturated fats into monounsaturated ones. It is precisely MCT oils such as coconut oil that increase omega oxidation of fats into dicarboxylic acids. I have now obtained the answer: it is support for gluconeogenesis and de novo lipogenesis, whose target products are glucose and oleic acid—an ideal combination of fuel!

And since saturated palmitic acid circulating in the blood under a normal diet is predominantly created by de novo lipogenesis from acetyl-CoA molecules, it means that at that moment the enzymes for its transformation into completely safe monounsaturated oleic acid are also active. If there is no problem with storing triglycerides in adipose tissue, there is nothing to worry about.

On the other hand, theoretically, the intake of palmitic acid in a low-carbohydrate diet, that is, without active lipogenesis and gluconeogenesis, could indeed be problematic. Fortunately, I do not know of any food that contains only palmitic acid while at the same time not containing enough oleic acid. Therefore, we can calmly conclude that the danger of saturated fatty acids is only a theoretical possibility, unrealizable in practice. We must look elsewhere for the causes of metabolic disorders.


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References:

Oleic Acid and Eicosapentaenoic Acid Reverse Palmitic Acid-Induced Insulin Resistance in Human HepG2 Cells via the Reactive Oxygen Species/JUN Pathway

Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPARα/γ activity in microvascular endothelial cells

Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes

Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum 


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