Do Omega-3s Really Act Against Omega-6s, or Is It the Effect of Acetate Against Fructose?

I’ll loosely follow up on an earlier post, where I examined the properties of fructose and acetate and how they act against each other. That post mainly dealt with enzyme acetylation — that is, the change of their “decoration” by an acetyl group. Fructose suppresses the deacetylase SIRT2 and probably also SIRT1. Acetate, on the other hand, activates SIRT1 and possibly SIRT2. Both substances thus act as regulators of the same processes, but in opposite directions. They therefore ensure balance. That’s important, because if there is an excess of one substance, its effect can be compensated by the other; we’re not left without a means of compensation — and that’s crucial.

Today I’d like to connect this model with the vicious cycle of obesity, as I described in previous posts. Few people realize that the effect of polyunsaturated oils on metabolism is, in fact, the effect of fructose produced via the polyol pathway in the liver through the presence of aldehydes such as 4-HNE. This is how a diet containing linoleic acid and seed oils changes metabolism. If we switch off the effect of fructose, the metabolic changes caused by polyunsaturated oils are small or almost nonexistent. Only the introduction of endogenous or dietary fructose changes the whole game.

Let’s go over it again — it’s a fairly complicated pathway. Fructose activates oxidative stress, which manifests as increased levels of H₂O₂. This peroxidizes all polyunsaturated fatty acids in the mitochondrial membrane — both omega-6 and omega-3 — but it does not affect saturated or monounsaturated fatty acids. Oxidative stress also activates iPLA2γ, which cleans the mitochondrial membrane of oxidized fatty acids and releases them as signaling molecules. Here we see the first difference: signaling molecules derived from omega-6 will differ from those derived from omega-3. They are removed by the same enzymes — AR and ALDH2. What interests us most is aldose reductase (AR). We know that it is activated by the aldehyde HNE, which is formed by peroxidation of linoleic or arachidonic acid. Could it also be activated by some product of omega-3 fatty acid peroxidation? Does it activate fructokinase? Even if omega-3s don’t activate AR, the production of fructose must already be triggered by the products of omega-6 lipid peroxidation. But we know that supplementing fish oil reduces obesity, so there must be something else involved. Is it acetate?

If we compare two studies on diabetic mice — that is, mice with high blood glucose levels, which certainly activate the hepatic polyol pathway — the results are practically identical. One study used fish oil, the other used sodium acetate.

PC – normal diet without diabetes, PD – normal diet with diabetes, SD – with fish oil and diabetes 


DAB+ with diabetes, SAT+ with sodium acetate

High glucose levels trigger the polyol pathway and activate fructokinase (KHK). We see high uric acid levels, meaning xanthine oxidase (XO) is active, producing H₂O₂. Supplementation with fish oil or sodium acetate nicely suppresses this pathway, lowers uric acid levels, and results in fewer peroxidized fatty acids. Is that similarity purely coincidental?

Let’s recall that fructose suppresses CPT1A, thereby blocking the transport of long-chain fats into mitochondria — they can’t then be used for immediate energy production. Since fish oil works and suppresses uric acid production, it must also suppress the effect of fructose. It must inhibit the enzyme AMPD2 and activate AMPK. We know that acetate can do this by activating the deacetylase SIRT1.

I found a study that explains that the link between fructose, SIRT1, and acetate is mediated by the enzyme ACSS2. This enzyme activates acetate for use in the cell by attaching CoA molecules to it. High glucose levels (HG) activate the polyol pathway, and fructose then activates ACSS2; inhibition of ACSS2 (ACSS2i) compensates the effects of fructose.

It is precisely fructose (HG+) that, through ACSS2 activation, triggers the chain leading to lipid synthesis. Inhibiting ACSS2 (ACSS2i+) compensates the fructose effect.

I’ve already discussed ACSS2 here in connection with fructose and amino acid deficiency. The study showed that ACSS2 is most active when amino acids are abundant (AA+) and in the presence of fructose (SIRT2 KD). Conversely, amino acid deficiency (AA−) decreases ACSS2 activity, and fructose then has almost no effect. If it works as shown in the previous diagram, then amino acid deficiency could reduce ACSS2 activity and suppress the effect of fructose. That’s one possible mechanism, but it’s unrelated to fish oil.

SIRT2 is regulated by fructose; KD represents a fructose-induced state; AA− indicates amino acid deficiency, AA+ indicates amino acid abundance.

So is acetate necessary to suppress the effect of fructose? Inhibiting ACSS2 activity raises acetate levels by blocking its use in new fat synthesis. Is acetate required for histone or sirtuin acetylation or deacetylation in order to counteract the effects of fructose?

So we probably do need an additional source of acetate — we need the right fats. But I haven’t found any fundamental difference between omega-3 and omega-6 in acetate production. Originally, I thought peroxisomes might be the source of acetate, since they preferentially process exotic, very long, and polyunsaturated fats. But mitochondria can do it too — at least rat mitochondria can do it quite well. Human mitochondria maybe not, but fish oil works in both. So that’s probably not the true source of acetate.

That leaves us with only one option — gut bacteria, which I’ve already written about. Polyunsaturated fats certainly help change the composition of gut bacteria and alter acetate production. Polyunsaturated fats are not direct substrates, but the desaturation of double bonds helps bacteria continue breaking down fiber into short-chain fatty acids, especially acetate. So I think our gut bacteria are the main players in suppressing the effects of fructose through omega-3 fats — and they do it via acetate.


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References:

Prophylactic Effect of Dietary Supplementation of Fish Oil Extracted from Sardinella Longiceps on Renal Dysfunction in Alloxan Induced Diabetic Mice (Mus Musculus)

Sodium acetate-mediated inhibition of histone deacetylase alleviates hepatic lipid dysregulation and its accompanied injury in streptozotocin-nicotinamide-induced diabetic rats

Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway

Partitioning of polyunsaturated fatty acid oxidation between mitochondria and peroxisomes in isolated rat hepatocytes studied by HPLC separation of oxidation products


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