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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage that includes hepatic dysfunction in over 50% of COVID-19 patients. Liver injury may result from cytopathic effects, immune responses, or drug toxicity. Here, we demonstrate that hepatocytes are susceptible to infection in models using primary hepatocytes from humanized ACE2 (hACE2) mice and primary human hepatocytes. Pseudotyped lentiviral particles expressing the full-length SARS-CoV-2 spike and recombinant receptor-binding domain (RBD) bind to ACE2 on hepatocytes, promoting metabolic reprogramming toward glycolysis and impairing mitochondrial activity. Human and hACE2 primary hepatocytes with steatosis and inflammation induced by methionine and choline deprivation are more vulnerable to infection. Inhibition of the renin-angiotensin system increases susceptibility of primary hepatocytes to spike-pseudotyped viral infection. Metformin, a therapy for hyperglycemia in type 2 diabetes that can attenuate fatty liver, reduces infection of human and hACE2 hepatocytes. These findings show hepatocyte susceptibility to SARS-CoV-2 spike-pseudovirus and suggest metformin could attenuate infection in patients with fatty liver.

Maria Mercado-Gómez, Endika Prieto-Fernández, Naroa Goikoetxea-Usandizaga, Laura Vila-Vecilla, Mikel Azkargorta, Miren Bravo, Marina Serrano-Maciá, Leire Egia-Mendikute, Rubén Rodríguez-Agudo, Sofia Lachiondo-Ortega, So Young Lee, Alvaro Eguileor Giné, Clàudia Gil-Pitarch, Irene González-Recio, Jorge Simón, Petar Petrov, Ramiro Jover, Luis Alfonso Martínez-Cruz, June Ereño-Orbea, Teresa Cardoso Delgado, Felix Elortza, Jesús Jiménez-Barbero, Ruben Nogueiras, Vincent Prevot, Asis Palazon, María L. Martínez-Chantar