Abstract
Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Betacoronavirus / immunology
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Betacoronavirus / pathogenicity*
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COVID-19
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Case-Control Studies
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Cholesterol / biosynthesis*
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Coronavirus Infections / genetics*
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Coronavirus Infections / immunology
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Coronavirus Infections / mortality
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Coronavirus Infections / virology
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Cytokine Release Syndrome / genetics*
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Cytokine Release Syndrome / immunology
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Cytokine Release Syndrome / mortality
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Cytokine Release Syndrome / virology
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Gene Expression Regulation
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / immunology
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Host-Pathogen Interactions / genetics*
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Host-Pathogen Interactions / immunology
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Humans
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Intensive Care Units
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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L-Lactate Dehydrogenase / genetics
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L-Lactate Dehydrogenase / immunology
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Leukocytes, Mononuclear / immunology*
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Leukocytes, Mononuclear / metabolism
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Leukocytes, Mononuclear / virology
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Lung / immunology
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Lung / metabolism
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Lung / virology
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NF-kappa B / genetics
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NF-kappa B / immunology
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Pandemics
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Pneumonia, Viral / genetics*
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Pneumonia, Viral / immunology
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Pneumonia, Viral / mortality
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Pneumonia, Viral / virology
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Primary Cell Culture
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Proprotein Convertase 9 / genetics
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Proprotein Convertase 9 / immunology
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SARS-CoV-2
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Signal Transduction
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Sterol Regulatory Element Binding Protein 2 / genetics*
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Sterol Regulatory Element Binding Protein 2 / immunology
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Survival Analysis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
Substances
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Heat-Shock Proteins
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IL1B protein, human
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Interleukin-1beta
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NF-kappa B
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SESN1 protein, human
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SREBF2 protein, human
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Sterol Regulatory Element Binding Protein 2
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Tumor Necrosis Factor-alpha
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Cholesterol
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L-Lactate Dehydrogenase
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PCSK9 protein, human
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Proprotein Convertase 9