Abstract
Enteric symptomology seen in early-stage severe acute respiratory syndrome (SARS)-2003 and COVID-19 is evidence of virus replication occurring in the intestine, liver and pancreas. Aberrant lipid metabolism in morbidly obese individuals adversely affects the COVID-19 immune response and increases disease severity. Such observations are in line with the importance of lipid metabolism in COVID-19, and point to the gut as a site for intervention as well as a therapeutic target in treating the disease. Formation of complex lipid membranes and palmitoylation of coronavirus proteins are essential during viral replication and assembly. Inhibition of fatty acid synthase (FASN) and restoration of lipid catabolism by activation of AMP-activated protein kinase (AMPK) impede replication of coronaviruses closely related to SARS-coronavirus-2 (CoV-2). In vitro findings and clinical data reveal that the FASN inhibitor, orlistat, and the AMPK activator, metformin, may inhibit coronavirus replication and reduce systemic inflammation to restore immune homeostasis. Such observations, along with the known mechanisms of action for these types of drugs, suggest that targeting fatty acid lipid metabolism could directly inhibit virus replication while positively impacting the patient’s response to COVID-19.
Highlights
All viruses repurpose cell catabolism and anabolism to generate energy and macromolecules for efficient replication; the mechanisms and consequences of SARScoronavirus-2 (CoV-2) lipid metabolic reprogramming is largely unexplored
severe acute respiratory syndrome (SARS)-CoV-2 replication relies on newly synthesized phospholipids or reengineered host membrane vesicles to serve as the replicative organelle that coordinates pairing of viral genomes and protein synthesis with virus assembly to complete the virus replication cycle [34,35,36,37]
While metformin’s actions on AMPK and mTORC1 lead to changes in glucose and protein metabolism, mitochondrial biogenesis and mitochondrial autophagy that may impact SARS-CoV-2 replication, we focused on metformin’s action on lipid metabolism
Summary
All viruses repurpose cell catabolism and anabolism to generate energy and macromolecules for efficient replication; the mechanisms and consequences of SARScoronavirus-2 (CoV-2) lipid metabolic reprogramming is largely unexplored. We examine fatty acid lipid metabolism in the context of COVID-19 at the organismal, cellular and macromolecular levels. With this basis of understanding, we propose two rational treatment options that directly target the virus’s lipid dependency as well as strengthen the patient’s response to SARS-CoV-2 infection
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