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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2
Journal of Pathology, Volume 254, No. 1, Year 2021
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Description
Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62–Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62–Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15–85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Authors & Co-Authors
Kilic, Konrad
Germany, Aachen
Uniklinik Rwth Aachen
Golob-Schwarzl, Nicole
Austria, Graz
Lkh-universitätsklinikum Graz
Preisinger, Christian
Germany, Aachen
Rheinisch-westfälische Technische Hochschule Aachen
George, Jacob A.
Australia, Parramatta
The Westmead Institute for Medical Research
Metwally, Mayada
Australia, Parramatta
The Westmead Institute for Medical Research
Eslam, Mohammed
Australia, Parramatta
The Westmead Institute for Medical Research
Lampertico, Pietro
Italy, Milan
Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
Petta, Salvatore
Italy, Palermo
Università Degli Studi Di Palermo
Mangia, A.
Italy, San Giovanni Rotondo
Irccs Casa Sollievo Della Sofferenza
Berg, Thomas
Germany, Leipzig
Universitätsklinikum Leipzig Und Medizinische Fakultät
Boonstra, André
Netherlands, Rotterdam
Erasmus Mc
Brouwer, Willem P.
Netherlands, Rotterdam
Erasmus Mc
Abate, Maria Lorena
Italy, Turin
Università Degli Studi Di Torino
Nahon, Pierre
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
France, Villetaneuse
University Sorbonne Paris Nord
France, Paris
Génomique Fonctionnelle Des Tumeurs Solides
Zoller, Heinz M.P.
Austria, Innsbruck
Medizinische Universitat Innsbruck
Aigner, Elmar S.
Austria, Salzburg
Paracelsus Medizinische Privatuniversitat
Trautwein, Christian
Germany, Aachen
Uniklinik Rwth Aachen
Haybaeck, Johannes
Germany, Magdeburg
Otto-von-guericke-universität Magdeburg
Austria, Innsbruck
Medizinische Universitat Innsbruck
Strnad, Pavel
Germany, Aachen
Uniklinik Rwth Aachen
Statistics
Citations: 2
Authors: 19
Affiliations: 18
Identifiers
Doi:
10.1002/path.5643
ISSN:
00223417
Research Areas
Cancer
Infectious Diseases
Violence And Injury
Study Design
Case-Control Study