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The spike of SARS-CoV-2 promotes metabolic rewiring in hepatocytes

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Mercado-Gomez, Maria
  • Prieto-Fernandez, Endika
  • Goikoetxea-Usandizaga, Naroa
  • Vila-Vecilla, Laura
  • Azkargorta, Mikel
  • Bravo, Miren
  • Serrano-Macia, Marina
  • Egia-Mendikute, Leire
  • Rodriguez-Agudo, Ruben
  • Lachiondo-Ortega, Sofia
  • Lee, So Young
  • Gine, Alvaro Eguileor
  • Gil-Pitarch, Claudia
  • Gonzalez-Recio, Irene
  • Simon, Jorge
  • Martinez-Cruz, Luis Alfonso
  • Ereno-Orbea, June
  • Delgado, Teresa Cardoso
  • Elortza, Felix
  • Jimenez-Barbero, Jesus
  • Nogueiras, Ruben
  • Prevot, Vincent
  • Palazon, Asis
  • Martinez-Chantar, Maria L.

Grupos

Abstract

SARS-CoV-2 pseudovirus infects human hepatocytes leading to metabolic reprogramming towards glycolysis and impaired mitochondrial activity, and metformin can reduce infection under steatotic conditions. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a multi-organ damage that includes hepatic dysfunction, which has been observed in over 50% of COVID-19 patients. Liver injury in COVID-19 could be attributed to the cytopathic effects, exacerbated immune responses or treatment-associated drug toxicity. Herein we demonstrate that hepatocytes are susceptible to infection in different models: primary hepatocytes derived from humanized angiotensin-converting enzyme-2 mice (hACE2) and primary human hepatocytes. Pseudotyped viral particles expressing the full-length spike of SARS-CoV-2 and recombinant receptor binding domain (RBD) bind to ACE2 expressed by hepatocytes, promoting metabolic reprogramming towards glycolysis but also impaired mitochondrial activity. Human and hACE2 primary hepatocytes, where steatosis and inflammation were induced by methionine and choline deprivation, are more vulnerable to infection. Inhibition of the renin-angiotensin system increases the susceptibility of primary hepatocytes to infection with pseudotyped viral particles. Metformin, a common therapeutic option for hyperglycemia in type 2 diabetes patients known to partially attenuate fatty liver, reduces the infection of human and hACE2 hepatocytes. In summary, we provide evidence that hepatocytes are amenable to infection with SARS-CoV-2 pseudovirus, and we propose that metformin could be a therapeutic option to attenuate infection by SARS-CoV-2 in patients with fatty liver.

© 2022. The Author(s).

Datos de la publicación

ISSN/ISSNe:
2399-3642, 2399-3642

Communications Biology  NATURE PORTFOLIO

Tipo:
Article
Páginas:
827-827
Factor de Impacto:
2,256 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 13

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Keywords

  • EXPRESSION; ACE2; ACCUMULATION; MITOCHONDRIA; PROTEIN

Proyectos asociados

DESARROLLO DE UN MODELO HEPATOCELULAR HUMANO DIFERENCIADO PARA ESTUDIOS DE METABOLISMO Y POTENCIAL INDUCTOR DE NUEVOS FARMACOS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

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DEVELOPMENT OF A HIGH THROUGHPUT GENOMICS-BASED TEST FOR ASSESSING GENOTOXIC AND CARCINOGENIC PROPERTIES OF CHEMICAL COMPOUNDS IN VITRO

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LINTOP

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Investigador Principal: RAMIRO JOVER ATIENZA

PI07/0550 . INSTITUTO DE SALUD CARLOS III . 2007

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Investigador Principal: RAMIRO JOVER ATIENZA

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Investigador Principal: RAMIRO JOVER ATIENZA

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Nuevos mecanismos y biomarcadores diagnósticos en la colestasis iatrogénica.

Investigador Principal: RAMIRO JOVER ATIENZA

PI17/01089 . INSTITUTO DE SALUD CARLOS III . 2018

Susceptibility factors and non-invasive biomarkers for liver steatosis induced by valproate in pediatric epileptic patients.

Investigador Principal: RAMIRO JOVER ATIENZA

PI20/00690 . INSTITUTO DE SALUD CARLOS III . 2021

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