Glutathione synthesis in mouse liver promotes lipid accumulation by inhibiting Nrf2

How to understand that "cell survival depends on antioxidants"

Glutathione (GSH) is a tripeptide composed of glutamic acid, cysteine and glycine, which is very high concentration in the cell and is the most important antioxidant in the cell.

The main role of glutathione is to remove free radicals (ROS) and protect cells from oxidative stress, and too much ROS accumulation can cause damage to the structure and function of cells.

Glutathione synthesis is non-redundant controlled by the glutamate-cysteine ligase catalytic subunit (GCLC).

Glutathione imbalance has been linked to many diseases, but the need for GSH in adult tissue is unknown.

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Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression

In June 2024, Published online by Nature Communications under the title "Glutathione synthesis in the mouse liver supports lipid abundance through Nrf2 repression" The research paper.

This study explored the association between GSH and liver lipid metabolism using GCLC conditional knockout mouse models and multiple omics methods, revealing that the core function of liver GSH synthesis is to promote lipid accumulation.

Project research

The research team cross-bred two genetically engineered mouse strains, Gclcf/f and Rosa26-CreERT2, to build a whole-body Gclc knockout (Gclc KO) KO model.

The absence of Gclc resulted in dramatic weight loss and decreased survival in mice, which was not seen in Gclc WT mice, suggesting that GSH is necessary to maintain survival in adult mice.

Glutathione deficiency led to weight loss and decreased survival in mice

The liver is one of the largest producers of GSH.

The authors examined liver tissue and serum biochemical markers of Gclc KO mice and found no damage to liver tissue.

Metabolomics analysis showed that in the absence of glutathione, the liver accumulates glutathione precursors and redirects them to other metabolic pathways.

Transcriptomic and proteomic analysis showed that the expression of proteins encoded by the Nrf2 gene and downstream target genes was increased in the liver of Gclc KO mice.

These results suggest that during glutathione depletion, the body may up-regulate the antioxidant pathway by activating Nrf2 to attenuate the oxidative stress damage induced by glutathione deficiency.

Gclc KO mice induced Nrf2 target gene expression and inhibited lipogenesis gene expression

The authors further investigated that after GSH consumption, lipogenesis gene expression was inhibited.

Consistent with this, Gclc KO mice also had lower triglyceride abundance. Low levels of triglycerides in Gclc KO mice were saved by a high-fat diet (HFD), but weight still showed a downward trend.

Lack of GSH synthesis in mice leads to decreased expression of the lipogenic enzyme (SCD1) and corresponding lipid species.

When mice were depleted of glutathione, triglyceride levels decreased

Is liver specific glutathione synthesis responsible for down-regulating lipogenic gene expression and lowering serum triglycerides?

The authors used the AAV-TBG-Cre virus delivery system to construct Gclc liver-specific knockout (GCLC-L-KO) mice.

It was found that the rapid depletion of Gclc mRNA and the gradual decline of Gclc protein and GSH levels in the liver of GCLC-L-KO mice resulted in increased Nrf2 activity, impaired lipogenic enzyme expression, decreased circulating triglycerides, and induced increased Nrf2 activity in a dose-dependent manner.

Liver-specific Gclc expression maintains lipid synthesis and inhibits Nrf2 activation

Subsequently, the authors constructed a double knockout (L-DKO) model of Gclc and Nrf2 in L-DKO mice. Gclc and Nrf2 mRNA levels decreased in L-DKO mice, and the phenotype of reduced lipid synthesis and reduced liver damage was reversed by Nrf2 knockout.

In other words, glutathione promotes lipid accumulation by inhibiting Nrf2 activation in the liver.

Glutathione in the liver maintains triglyceride levels in an NrF2-dependent manner

Research conclusion

Glutathione levels are highest in liver tissue, which is also the center of lipid production.

Although the loss of glutathione does not lead to liver failure, it reduces the expression of lipogenic enzymes, circulating triglyceride levels, and fat storage.

Mechanistically, the study found that glutathione promotes lipid abundance by inhibiting oxidative stress-induced transcription factor NRF2.

These studies identified glutathione as the fulcrum for the balance of REDOX buffering and triglyceride production in the liver.