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Copy number variation and expression of exportin-4 associates with severity of fibrosis in metabolic associated fatty liver disease.
Metwally, Mayada; Bayoumi, Ali; Khan, Anis; Adams, Leon A; Aller, Rocio; García-Monzón, Carmelo; Arias-Loste, María Teresa; Bugianesi, Elisabetta; Miele, Luca; Anna, Alisi; Latchoumanin, Olivier; Han, Shuanglin; Alenizi, Shafi; Sharkawy, Rasha El; Elattar, Afaf; Gallego-Durán, Rocio; Fischer, Janett; Berg, Thomas; Liddle, Christopher; Romero-Gomez, Manuel; George, Jacob; Eslam, Mohammed.
Afiliação
  • Metwally M; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Bayoumi A; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Khan A; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Adams LA; Medical School, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia.
  • Aller R; Center of Investigation of Endocrinology and Nutrition, School of Medicine, and Unit of Investigation, Hospital Clinico Universitario de Valladolid, Valladolid, Spain.
  • García-Monzón C; Liver Research Unit, Instituto de Investigacion Sanitaria Princesa, University Hospital Santa Cristina, CIBERehd, Madrid, Spain.
  • Arias-Loste MT; Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain.
  • Bugianesi E; Division of Gastroenterology, Department of Medical Science, University of Turin, Turin, Italy.
  • Miele L; Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy.
  • Anna A; Research Unit of Molecular Genetics of Complex Phenotypes, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy.
  • Latchoumanin O; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Han S; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Alenizi S; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Sharkawy RE; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Elattar A; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Gallego-Durán R; Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, Sevilla, Spain.
  • Fischer J; Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.
  • Berg T; Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.
  • Liddle C; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
  • Romero-Gomez M; Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, Sevilla, Spain.
  • George J; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address: jacob.george@sydney.edu.au.
  • Eslam M; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address: mohammed.eslam@sydney.edu.au.
EBioMedicine ; 70: 103521, 2021 Aug.
Article em En | MEDLINE | ID: mdl-34388518
ABSTRACT

BACKGROUND:

Liver fibrosis risk is a heritable trait, the outcome of which is the net deposition of extracellular matrix by hepatic stellate cell-derived myofibroblasts. Whereas nucleotide sequence variations have been extensively studied in liver fibrosis, the role of copy number variations (CNV) in which genes exist in abnormal numbers of copies (mostly due to duplication or deletion) has had limited exploration.

METHODS:

The impact of the XPO4 CNV on histological liver damage was examined in a cohort comprised 646 Caucasian patients with biopsy-proven MAFLD and 170 healthy controls. XPO4 expression was modulated and function was examined in human and animal models.

FINDINGS:

Here we demonstrate in a cohort of 816 subjects, 646 with biopsy-proven metabolic associated liver disease (MAFLD) and 170 controls, that duplication in the exportin 4 (XPO4) CNV is associated with the severity of liver fibrosis. Functionally, this occurs via reduced expression of hepatic XPO4 that maintains sustained activation of SMAD3/SMAD4 and promotes TGF-ß1-mediated HSC activation and fibrosis. This effect was mediated through termination of nuclear SMAD3 signalling. XPO4 demonstrated preferential binding to SMAD3 compared to other SMADs and led to reduced SMAD3-mediated responses as shown by attenuation of TGFß1 induced SMAD transcriptional activity, reductions in the recruitment of SMAD3 to target gene promoters following TGF-ß1, as well as attenuation of SMAD3 phosphorylation and disturbed SMAD3/SMAD4 complex formation.

INTERPRETATION:

We conclude that a CNV in XPO4 is a critical mediator of fibrosis severity and can be exploited as a therapeutic target for liver fibrosis.

FUNDING:

ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). AB is supported by an Australian Government Research Training Program (RTP) scholarship. EB is supported by Horizon 2020 under grant 634413 for the project EPoS.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carioferinas / Fígado Gorduroso / Variações do Número de Cópias de DNA / Cirrose Hepática Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carioferinas / Fígado Gorduroso / Variações do Número de Cópias de DNA / Cirrose Hepática Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália