PMID- 35521658
OWN - NLM
STAT- MEDLINE
DCOM- 20230126
LR  - 20230209
IS  - 1557-7716 (Electronic)
IS  - 1523-0864 (Linking)
VI  - 38
IP  - 1-3
DP  - 2023 Jan
TI  - RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly 
      Inducing TNFalpha.
PG  - 137-159
LID - 10.1089/ars.2021.0174 [doi]
AB  - Aims: 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) alpha/gamma 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. Results: 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 alpha (TNFalpha) from isolated 
      hepatocytes, stellate cells and its depletion reverses steatosis, oxidative 
      stress by direct TNFalpha exposure. Conversely, RGS7 overexpression in the liver is 
      sufficient to trigger oxidative stress in hepatocytes that can be mitigated via 
      TNFalpha inhibition. Innovation: 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. Conclusion: RGS7 represents a 
      potential novel target for the amelioration of NAFLD. Antioxid. Redox Signal. 38, 
      137-159.
FAU - Basak, Madhuri
AU  - Basak M
AD  - Centre of Biomedical Research, Lucknow, India.
FAU - Das, Kiran
AU  - Das K
AD  - Centre of Biomedical Research, Lucknow, India.
FAU - Mahata, Tarun
AU  - Mahata T
AD  - Centre of Biomedical Research, Lucknow, India.
FAU - Sengar, Abhishek Singh
AU  - Sengar AS
AD  - Centre of Biomedical Research, Lucknow, India.
FAU - Verma, Sumit Kumar
AU  - Verma SK
AD  - Centre of Biomedical Research, Lucknow, India.
FAU - Biswas, Sayan
AU  - Biswas S
AD  - Department of Forensic Medicine, College of Medicine and Sagore Dutta Hospital, 
      Kolkata, India.
FAU - Bhadra, Kakali
AU  - Bhadra K
AD  - Department of Zoology, University of Kalyani, Kalyani, India.
FAU - Stewart, Adele
AU  - Stewart A
AD  - Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida 
      Atlantic University, Jupiter, Florida, USA.
FAU - Maity, Biswanath
AU  - Maity B
AUID- ORCID: 0000-0002-3239-3764
AD  - Centre of Biomedical Research, Lucknow, India.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220701
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - 0 (RGS Proteins)
RN  - 0 (Rgs7 protein, mouse)
RN  - E0YMX3S4JD (saroglitazar)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Atf3 protein, mouse)
RN  - EC 2.3.1.48 (Kat5 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Diet, High-Fat
MH  - Inflammation/metabolism
MH  - Liver/metabolism
MH  - Liver Cirrhosis/metabolism
MH  - Mice, Inbred C57BL
MH  - *Non-alcoholic Fatty Liver Disease/metabolism
MH  - *RGS Proteins/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
OTO - NOTNLM
OT  - NAFLD
OT  - NASH
OT  - RGS proteins
OT  - TNFalpha
OT  - inflammation
OT  - oxidative stress
EDAT- 2022/05/07 06:00
MHDA- 2023/01/20 06:00
CRDT- 2022/05/06 06:22
PHST- 2022/05/07 06:00 [pubmed]
PHST- 2023/01/20 06:00 [medline]
PHST- 2022/05/06 06:22 [entrez]
AID - 10.1089/ars.2021.0174 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2023 Jan;38(1-3):137-159. doi: 10.1089/ars.2021.0174. Epub 
      2022 Jul 1.