ArticleRedox biology2021
Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death.
Article in Redox biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 29 citations in OpenAlex.
- Identification of shared genetic architecture between non-alcoholic fatty liver disease and type 2 diabetes: A genome-wide analysis.Frontiers in endocrinology · 2023Pooled it
- Identification of Gβ5 Interactome Associated with Neuronal Development in Neuro-2a Cells through miniTurbo Proximity Labeling.ACS omega · 2026Article
- RGS16 Aggravates Hepatic Ischemia-Reperfusion Injury via Hepatocyte-Intrinsic Apoptosis/Inflammation & Neutrophil Recruitment/NETosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Suicide risk genes impact evolutionarily conserved survival strategies.Translational psychiatry · 2026Article
- NRF1 is upregulated by docosahexaenoic acid to ameliorate MASH through the inhibition of ER stress.Cell death & disease · 2026Article
- Suicide risk genes impact evolutionarily conserved survival strategies.Research square · 2025Article
- Redox regulation: mechanisms, biology and therapeutic targets in diseases.Signal transduction and targeted therapy · 2025Review
- Article
- Immune infiltration analysis based on pyroptosis-related gene in metabolic dysfunction-associated fatty liver disease.Heliyon · 2024Article
- RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21.Journal of translational medicine · 2024Article
- TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production.International journal of biological sciences · 2024Article
- Regulator of G protein signaling protein 6 alleviates acute lung injury by inhibiting inflammation and promoting cell self-renewal in mice.Cellular & molecular biology letters · 2023Article
- RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation.Cellular and molecular life sciences : CMLS · 2023Article
- Article
- A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- RGS6 Drives Spinal Cord Injury by Inhibiting AMPK Pathway in Mice.Disease markers · 2022Article
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Authors and funding
14 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The pathophysiological mechanism(s) driving non-alcoholic fatty liver disease, the most prevalent chronic liver disease globally, have yet to be fully elucidated. Here, we identify regulator of G protein signaling 6 (RGS6), up-regulated in the livers of NAFLD patients, as a critical mediator of hepatic steatosis, fibrosis, inflammation, and cell death. Human patients with high hepatic RGS6 expression exhibited a corresponding high inflammatory burden, pronounced insulin resistance, and poor liver function. In mice, liver-specific RGS6 knockdown largely ameliorated high fat diet (HFD)-driven oxidative stress, fibrotic remodeling, inflammation, lipid deposition and cell death. RGS6 depletion allowed for maintenance of mitochondrial integrity restoring redox balance, improving fatty acid oxidation, and preventing loss of insulin receptor sensitivity in hepatocytes. RGS6 is both induced by ROS and increases ROS generation acting as a key amplification node to exacerbate oxidative stress. In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation. pATM and markers of DNA damage (γH2AX) were also elevated in livers from NAFLD patients particularly in samples with high RGS6 protein content. Unsurprisingly, RGS6 knockdown prevented ATM phosphorylation in livers from HFD-fed mice. Further, RGS6 mutants lacking the capacity for ATM binding fail to facilitate palmitic acid-dependent hepatocyte apoptosis underscoring the importance of the RGS6-ATM complex in hyperlipidemia-dependent cell death. Inhibition of RGS6, then, may provide a viable means to prevent or reverse liver damage by mitigating oxidative liver damage.
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Registered trials
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