期刊
CELL DISCOVERY
卷 7, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41421-021-00338-2
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资金
- RGC General Research Fund [17119821, 17126919]
- Innovation and Technology Fund (ITF), Innovation and Technology Commission, the Government of the Hong Kong Special Administrative Region
- National Program on Key Research Project of China [2020YFA0707500, 2020YFA0707504]
- Sanming Project of Medicine in Shenzhen, China [SZSM201911014]
- High Level-Hospital Program, Health Commission of Guangdong Province, China
The study found that triglycerides in the plasma lipidome of COVID-19 patients are the dominant lipids in metabolic dysregulation, with the key enzymes DGAT and stabilizer ADRP being essential for virus replication. Depletion of DGAT gene reduces virus protein synthesis without affecting genome replication. An inhibitor called xanthohumol was able to suppress virus replication and pulmonary inflammation in a hamster model.
Coronavirus Disease 2019 (COVID-19) is predominantly a respiratory tract infection that significantly rewires the host metabolism. Here, we monitored a cohort of COVID-19 patients' plasma lipidome over the disease course and identified triacylglycerol (TG) as the dominant lipid class present in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced metabolic dysregulation. In particular, we pinpointed the lipid droplet (LD)-formation enzyme diacylglycerol acyltransferase (DGAT) and the LD stabilizer adipocyte differentiation-related protein (ADRP) to be essential host factors for SARS-CoV-2 replication. Mechanistically, viral nucleo capsid protein drives DGAT1/2 gene expression to facilitate LD formation and associates with ADRP on the LD surface to complete the viral replication cycle. DGAT gene depletion reduces SARS-CoV-2 protein synthesis without compromising viral genome replication/transcription. Importantly, a cheap and orally available DGAT inhibitor, xanthohumol, was found to suppress SARS-CoV-2 replication and the associated pulmonary inflammation in a hamster model. Our findings not only uncovered the mechanistic role of SARS-CoV-2 nucleocapsid protein to exploit LDs-oriented network for heightened metabolic demand, but also the potential to target the LDs-synthetase DGAT and LDs-stabilizer ADRP for COVID-19 treatment.
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