Hydrogen Sulfide as a Metabolic Repairman?

In the previous post we saw how the restriction of sulfur-containing amino acids works in a mouse model. Restricting them to one-sixth essentially prevents fat formation and storage, and re-supplementation almost immediately starts to restore fat stores again—very interesting. A similar effect is seen with overall protein restriction in the diet, as we have already noted.

I was thinking about possible mechanisms and almost forgot about the post where I commented on a study linking the (in)sufficiency of amino acids, the deacetylase SIRT2, and the effects of fructose—specifically the effect of activation of the enzyme KHK, which phosphorylates fructose. The conclusion of that reasoning was that amino acid deficiency activates SIRT2 and thereby limits fat formation. This manifests itself through deacetylation and removal of the enzyme ACSS2, which activates acetate into acetyl-CoA—thus reducing the production of substrates for new fat synthesis. But fructose, via KHK, suppresses SIRT2 and thus potentially cancels out the effect of amino acid deficiency and increases fat synthesis.

This led me to look for connections between sulfur and the deacetylases called sirtuins. And I found a whole range of very recent studies examining the effects of hydrogen sulfide (H₂S) on lipid and glucose metabolism. H₂S is produced during the processing of sulfur amino acids, e.g., by the enzyme cystathionine-γ-lyase CSE/CGL. It acts by replacing the ubiquitin “decoration” of some sirtuins with their sulfhydration. It looks like this topic will need more than just this one post—it is truly large and complex.

So let’s begin with the deacetylase SIRT1 and its connections with cardiovascular disease. We will use the results of a study in mice.

The mechanism by which hydrogen sulfide influences enzyme acetylation so that it suppresses cholesterol synthesis, reduces inflammation, and limits plaque formation in blood vessels.

The study demonstrates the reduction of atherosclerotic plaque through H₂S, using a mouse model of atherosclerosis, and shows the effects of hydrogen sulfide via two compounds that generate H₂S in the body (NaHS or GYY4137).

H₂S activates SIRT1, suppresses inflammation, repairs lipid metabolism in the aorta and liver.

Thus, the study shows that activating the deacetylase SIRT1 can be used, for example, to address atherosclerosis. I have already written several times here about studies with acetate, where the effect depended on the expression of SIRT1. Even cellular aging of the vascular endothelium was reduced. We know that in this case too, the effects of acetate are mediated precisely by SIRT1. In another post, acetate via SIRT1 was shown to address pulmonary silicofibrosis or fatty liver disease.

The main natural enzymatic source of H₂S is the enzyme CSE, cystathionine-γ-lyase. Increased expression of CSE (Ad-CSE) results in the activation of SIRT1 production, while suppression of expression (siRNA-CSE) results in deactivation of SIRT1 production.

Now we can recall the previous post that examined the effects of restricting sulfur amino acids—specifically cysteine and methionine. In the figure comparing levels of certain metabolites, it was possible to identify that although dietary intake of cyst(e)ine was substantially lower, the fasting level of cystathionine and cysteine in the liver was higher. This would allow greater use of cysteine for H₂S production and activation of SIRT1, thus ensuring higher production of NADPH molecules and better recycling of glutathione (GSH).

If I were to outline a certain summary with the insight into the general benefits of hydrogen sulfide on cellular metabolism, it seems most likely to me that the effect of protein restriction is in fact the effect of activating hydrogen sulfide production with subsequent activation of the deacetylases SIRT1, SIRT2, SIRT3, and possibly others. This fundamentally changes the acetylation and activity of many enzymes and can therefore address many health problems.


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References:

Sulfhydrated Sirtuin-1 Increasing Its Deacetylation Activity Is an Essential Epigenetics Mechanism of Anti-Atherogenesis by Hydrogen Sulfide



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