RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly Inducing TNFα

Madhuri Basak; Kiran Das; Tarun Mahata; Abhishek Singh Sengar; Sumit Kumar Verma; Sayan Biswas; Kakali Bhadra; Adele Stewart; Biswanath Maity

doi:10.1089/ars.2021.0174

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RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly Inducing TNFα

Journal article

Peer reviewed

RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly Inducing TNFα

Madhuri Basak, Kiran Das, Tarun Mahata, Abhishek Singh Sengar, Sumit Kumar Verma, Sayan Biswas, Kakali Bhadra, Adele Stewart and Biswanath Maity

Antioxidants & redox signaling, Vol.38(1-3), pp.137-159

01/2023

DOI: 10.1089/ars.2021.0174

PMID: 35521658

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Abstract

The pathophysiological mechanism(s) underlying non-alcoholic fatty liver disease (NAFLD) have yet to be fully delineated and only a single drug, peroxisome proliferator-activated receptor (PPAR) α/γ agonist saroglitazar, has been approved. Here, we sought to investigate the role of Regulator of G Protein Signaling 7 (RGS7) in hyperlipidemia-dependent hepatic dysfunction. RGS7 is elevated in the livers of NAFLD patients, particularly those with severe hepatic damage, pronounced insulin resistance, and high inflammation. In the liver, RGS7 forms a unique complex with transcription factor ATF3 and histone acetyltransferase Tip60, which is implicated in NAFLD. The removal of domains is necessary for ATF3/Tip60 binding compromises RGS7-dependent reactive oxygen species generation and cell death. Hepatic RGS7 knockdown (KD) prevented ATF3/Tip60 induction, and it provided protection against fibrotic remodeling and inflammation in high-fat diet-fed mice translating to improvements in liver function. Hyperlipidemia-dependent oxidative stress and metabolic dysfunction were largely reversed in RGS7 KD mice. Interestingly, saroglitazar failed to prevent RGS7/ATF3 upregulation but it did partially restore Tip60 levels. RGS7 drives the release of particularly tumor necrosis factor α (TNFα) from isolated hepatocytes, stellate cells and its depletion reverses steatosis, oxidative stress by direct TNFα exposure. Conversely, RGS7 overexpression in the liver is sufficient to trigger oxidative stress in hepatocytes that can be mitigated TNFα inhibition. We discovered a novel non-canonical function for an R7RGS protein, which usually functions to regulate G protein coupled receptor (GPCR) signaling. This is the first demonstration for a functional role of RGS7 outside the retina and central nervous system. RGS7 represents a potential novel target for the amelioration of NAFLD. 38, 137-159.

Animals

Diet, High-Fat

Inflammation - metabolism

Liver - metabolism

Liver Cirrhosis - metabolism

Mice

Mice, Inbred C57BL

Non-alcoholic Fatty Liver Disease - metabolism

RGS Proteins - genetics

RGS Proteins - metabolism

Tumor Necrosis Factor-alpha - metabolism

Details

Title: Subtitle: RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly Inducing TNFα
Creators: Madhuri Basak - Centre of Biomedical Research
Kiran Das - Centre of Biomedical Research
Tarun Mahata - Centre of Biomedical Research
Abhishek Singh Sengar - Centre of Biomedical Research
Sumit Kumar Verma - College of Medicine & Sagore Dutta Hospital
Sayan Biswas - University of Kalyani
Kakali Bhadra - Florida Atlantic University
Adele Stewart - Centre of Biomedical Research
Biswanath Maity - Centre of Biomedical Research
Resource Type: Journal article
Publication Details: Antioxidants & redox signaling, Vol.38(1-3), pp.137-159
DOI: 10.1089/ars.2021.0174
PMID: 35521658
ISSN: 1523-0864
eISSN: 1557-7716
Language: English
Date published: 01/2023
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984618643002771

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