tetano
Editor, Senior Moderator
Commun Biol
. 2022 Aug 17;5(1):827.
doi: 10.1038/s42003-022-03789-9.
The spike of SARS-CoV-2 promotes metabolic rewiring in hepatocytes
Maria Mercado-Gómez[SUP] #[/SUP][SUP] 1 [/SUP], Endika Prieto-Fernández[SUP] #[/SUP][SUP] 2 [/SUP], Naroa Goikoetxea-Usandizaga[SUP] 1 [/SUP], Laura Vila-Vecilla[SUP] 2 [/SUP], Mikel Azkargorta[SUP] 3 4 [/SUP], Miren Bravo[SUP] 1 [/SUP], Marina Serrano-Maciá[SUP] 1 [/SUP], Leire Egia-Mendikute[SUP] 2 [/SUP], Rubén Rodríguez-Agudo[SUP] 1 [/SUP], Sofia Lachiondo-Ortega[SUP] 1 [/SUP], So Young Lee[SUP] 2 [/SUP], Alvaro Eguileor Giné[SUP] 1 [/SUP], Clàudia Gil-Pitarch[SUP] 1 [/SUP], Irene González-Recio[SUP] 1 [/SUP], Jorge Simón[SUP] 1 4 [/SUP], Petar Petrov[SUP] 4 5 [/SUP], Ramiro Jover[SUP] 4 5 6 [/SUP], Luis Alfonso Martínez-Cruz[SUP] 1 [/SUP], June Ereño-Orbea[SUP] 7 8 9 [/SUP], Teresa Cardoso Delgado[SUP] 1 [/SUP], Felix Elortza[SUP] 3 4 [/SUP], Jesús Jiménez-Barbero[SUP] 7 8 9 10 [/SUP], Ruben Nogueiras[SUP] 11 [/SUP], Vincent Prevot[SUP] 12 [/SUP], Asis Palazon[SUP] 13 14 [/SUP], María L Martínez-Chantar[SUP] 15 16 [/SUP]
Affiliations
Abstract
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 Aug 17;5(1):827.
doi: 10.1038/s42003-022-03789-9.
The spike of SARS-CoV-2 promotes metabolic rewiring in hepatocytes
Maria Mercado-Gómez[SUP] #[/SUP][SUP] 1 [/SUP], Endika Prieto-Fernández[SUP] #[/SUP][SUP] 2 [/SUP], Naroa Goikoetxea-Usandizaga[SUP] 1 [/SUP], Laura Vila-Vecilla[SUP] 2 [/SUP], Mikel Azkargorta[SUP] 3 4 [/SUP], Miren Bravo[SUP] 1 [/SUP], Marina Serrano-Maciá[SUP] 1 [/SUP], Leire Egia-Mendikute[SUP] 2 [/SUP], Rubén Rodríguez-Agudo[SUP] 1 [/SUP], Sofia Lachiondo-Ortega[SUP] 1 [/SUP], So Young Lee[SUP] 2 [/SUP], Alvaro Eguileor Giné[SUP] 1 [/SUP], Clàudia Gil-Pitarch[SUP] 1 [/SUP], Irene González-Recio[SUP] 1 [/SUP], Jorge Simón[SUP] 1 4 [/SUP], Petar Petrov[SUP] 4 5 [/SUP], Ramiro Jover[SUP] 4 5 6 [/SUP], Luis Alfonso Martínez-Cruz[SUP] 1 [/SUP], June Ereño-Orbea[SUP] 7 8 9 [/SUP], Teresa Cardoso Delgado[SUP] 1 [/SUP], Felix Elortza[SUP] 3 4 [/SUP], Jesús Jiménez-Barbero[SUP] 7 8 9 10 [/SUP], Ruben Nogueiras[SUP] 11 [/SUP], Vincent Prevot[SUP] 12 [/SUP], Asis Palazon[SUP] 13 14 [/SUP], María L Martínez-Chantar[SUP] 15 16 [/SUP]
Affiliations
- PMID: 35978143
- DOI: 10.1038/s42003-022-03789-9
Abstract
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.