Is the play between fructose and acetate a play between the deacetylases SIRT2 and SIRT1?

I have mentioned the positive effects of acetic acid and sodium acetate on metabolism many times here. Studies show that if the negative consequences of a high-fat diet are caused by fructose, i.e., the fructose contained in sucrose or produced in the liver from glucose (practically always), then sodium acetate often manages to reverse this effect in rodents, resulting in positive effects such as fat burning and weight loss. Mice, therefore, lose weight, normalize blood sugar and insulin levels, etc. We have also shown that the negative effects of fructose in combination with fats are caused by acetylation, specifically by the suppression of deacetylation by the enzyme SIRT2. This, among other things, causes the loss of CPT1 carnitine transporter molecules for the transport of long-chain fatty acids into mitochondria, so the fats must be stored.

Fructose activates the enzyme KHK-C, and its increased presence (KHK-C OE) suppresses the enzyme deacetylase SIRT2. Thus, fructose prevents fat burning and activates fat storage.

I found a study that confirms that the main effect of bifidobacteria is the production of acetate when examining the impact of the gut microbiome on pulmonary silicofibrosis. Acetate passes through the intestinal wall into the systemic bloodstream and has a protective effect against silicofibrosis. The same effect is achieved with administered sodium acetate, and it was also shown that the deactivation of the enzyme SIRT1 cancels these positive effects. Thus, acetate works through the activation of SIRT1, which then deacetylates several enzymes and proteins. For us, the deacetylation of the enzyme LKB1 is interesting because it phosphorylates and activates AMPK, thereby suppressing ACC, i.e., de novo lipogenesis and obesity. It seems that the game between fructose and acetate is a game between the deactivation of SIRT2 and the activation of SIRT1.

In the model of pulmonary silicofibrosis, it can be traced that dietary sodium acetate (NaAc) restores AMPK activity (pAMPK)...

....through the activation of deacetylase SIRT1. Genetic shutdown of SIRT1 (NA-EX) also shuts down the positive effects of sodium acetate (NaAc).

We are not limited to one study. Another study examined the effects of metabolites produced by the bacteria Akkermansia muciniphila on liver disease associated with metabolic fat (MASH, formerly non-alcoholic fatty liver disease NASH). This one sentence from the study may be sufficient:

"The present study identified acetate as a key A.muc-derived metabolite that activates hepatic AMPK signaling to ameliorate lipid peroxidation and ferroptosis."

Akkermansia muciniphila (A.muc) activates ACSS1, which converts acetate into acetyl-CoA, which also helps to activate AMPK by increasing AMP.

The increase in AMP is the highest for Akkermansia muciniphila (A.muc).

The concentration of acetate in the liver is by far the highest of all SCFAs.
.

When activated, acetate produces the most AMP for stimulating AMPK. It also protects the most against peroxidation (MDA) and restores the most reduced glutathione (GSH).

Acetate activates deacetylase SIRT1 the most.

Acetic acid is always the most abundant.

In different tissues, the values are different; Akkermansia muciniphila is most prominent in the front part of the large intestine (Ileum).

Akkermansia muciniphila restores levels disrupted by a high-fat, high-fructose diet (HFHFD).

A high-fat, high-fructose diet (HFHFD) activates the immune system and chronic inflammation (NOX2) and pseudohypoxia/senescence.

Therefore, the main product of the bacterium Akkermansia muciniphila is acetate. The positive effects they mention include the reduction of lipid peroxidation (i.e., polyunsaturated) and the suppression of ferroptosis, i.e., cell death caused by iron oxidation in mice on a high-fat, high-fructose diet. The mechanism is the same as for the suppression of silicofibrosis effects mentioned above. It is the activation of deacetylase SIRT1, which deacetylates the kinase LKB1, which then phosphorylates the kinase AMPK. AMPK phosphorylates ACC and reduces the formation of new fats. This saves NADPH for the restoration of reduced glutathione GSH and increases antioxidant protection. Only then can the normal regulation of oxidative phosphorylation through hydrogen peroxide H2O2, PLA2, and UCP begin to function.

An overarching mechanism is beginning to emerge by which gut bacteria positively affect metabolism. It is acetylation and activation or deactivation of deacetylases. It is time to set aside gut butyrate as a byproduct that, although it also works, its excessive activity is dangerous, and high concentration is outright harmful. More research should be dedicated to microbial-origin acetate, but also to the effects of sodium acetate, triacetin, or diluted vinegar supplementation. There is ample evidence in rodents; now, research needs to be conducted in humans to determine appropriate dosages and therapies.


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References:

Activation of Sirt1 by acetate alleviates silicofibrosis: Contribution of the gut microbiota

SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation

Ketohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation

Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease


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