Journal article
Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death
Redox biology, Vol.46, pp.102105-102105
10/01/2021
DOI: 10.1016/j.redox.2021.102105
PMCID: PMC8446788
PMID: 34534913
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.
Details
- Title: Subtitle
- Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death
- Creators
- Tarun Mahata - Centre of Biomedical ResearchAbhishek Singh Sengar - Sanjay Gandhi Post Graduate Institute of Medical SciencesMadhuri Basak - Centre of Biomedical ResearchKiran Das - Centre of Biomedical ResearchArnab Pramanick - Sanjay Gandhi Post Graduate Institute of Medical SciencesSumit Kumar Verma - Sanjay Gandhi Post Graduate Institute of Medical SciencesPraveen Kumar Singh - University of MiamiSayan Biswas - College of Medicine & Sagore Dutta HospitalSubhasish Sarkar - College of Medicine & Sagore Dutta HospitalSudipta Saha - Babasaheb Bhimrao Ambedkar UniversitySuvro Chatterjee - Anna University, ChennaiMadhusudan Das - University of CalcuttaAdele Stewart - Florida Atlantic UniversityBiswanath Maity - Centre of Biomedical Research
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.46, pp.102105-102105
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.redox.2021.102105
- PMID
- 34534913
- PMCID
- PMC8446788
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Language
- English
- Date published
- 10/01/2021
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618642702771
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