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Senescent hepatocytes in decompensated liver show reduced UPR<sup>MT</sup> and its key player, CLPP, attenuates senescence in vitro

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Title Senescent hepatocytes in decompensated liver show reduced UPRMT and its key player, CLPP, attenuates senescence in vitro
CLPP attenuates hepatocyte senescence
 
Creator Sen, Bijoya
Rastogi, Archana
Nath, Rhisita
Shasthry, Saggere M.
Pamecha, Viniyendra
Pandey, Sonika
Gupta, Kapuganti Jagadis
Sarin, Shiv K.
Trehanpati, Nirupma
Ramakrishna, Gayatri
 
Subject Cryptogenic liver cirrhosis
Mitochondrial respiration
Mitochondrial unfolded protein response
Oxidative stress
 
Description Accepted date: 1 March 2019
Background and Aims
Non-dividing hepatocytes in end-stage liver disease indicates permanent growth arrest similar to senescence. Identifying senescence in vivo is often challenging and mechanisms inhibiting senescence are poorly understood. In lower organisms mitochondrial unfolded protein response (UPRMT) helps in increasing longevity; however, its role in senescence and liver disease is poorly understood. Aim of this study was to identify hepatocyte senescence and role of UPRMT in cryptogenic cirrhosis.

Methods
Doxorubicin was used to induce senescence in non-neoplastic hepatocytes (PH5CH8) and hepatoma cells (HepG2 and Huh7). Senescence-associated markers and unfolded protein response was evaluated by fluorescence microscopy, immunoblotting and gene expression. Explants/biopsies from normal, fibrosis, compensated and decompensated cirrhosis without any known etiology were examined for presence of senescence and UPRMT by immunohistochemistry and gene expression.

Results
Accumulation of senescent hepatocytes in cryptogenic cirrhosis was associated with reduced proliferation, increased expression of γH2AX and p21, together with loss of LaminB1. Dysfunctional mitochondria and compromised UPRMT were key features of senescent hepatocytes both in vitro and also in decompensated cirrhosis. Intriguingly, compensated cirrhotic liver mounted strong UPRMT, with high levels of mitochondrial protease, CLPP. Over-expression of CLPP inhibited senescence in vitro, by reducing mitochondrial ROS and altering oxygen consumption.

Conclusions
Our results implicate a role of hepatocyte senescence in cryptogenic cirrhosis together with a crucial role of UPRMT in preventing hepatocyte senescence. A compromised UPRMT may shift the fate of cirrhotic liver towards decompensation by exaggerating hepatocyte senescence. Restoring CLPP levels at least in cell culture appears as a promising strategy in mitohormesis, thereby, preventing senescence and possibly improving hepatocyte function.
We thank Prof. T Ramasarma and Dr. Lucy Anderson for critical reading and editing of the
manuscript. BS is a recipient of UGC senior research fellowship. We thank Dr. Nobuyuki Kato,
Okayama University for providing us the PH5CH8 cells. We thank DST-FIST for support. We also
thank the anonymous reviewers for their valuable inputs.
 
Date 2019-03-20T09:29:03Z
2019-03-20T09:29:03Z
2019
 
Type Article
 
Identifier Cellular and Molecular Gastroenterology and Hepatology, 8: 73-94
2352-345X
http://223.31.159.10:8080/jspui/handle/123456789/932
https://www.sciencedirect.com/science/article/pii/S2352345X1930027X?via%3Dihub
https://doi.org/10.1016/j.jcmgh.2019.03.001
 
Language en_US
 
Format application/pdf
 
Publisher Elsevier B.V.