The CH24H metabolite, 24HC, blocks viral entry by disrupting intracellular cholesterol homeostasis

Yuan, Yueming; Fang, An; Wang, Zongmei; Wang, Zhihui; Sui, Baokun; Zhu, Yangyong; Zhang, Yuan; Wang, Caiqian; Zhang, Rong; Zhou, Ming; Chen, Huanchun; Fu, Zhen F.; Zhao, Ling

doi:10.1016/j.redox.2023.102769

Cited by 3 publications

(1 citation statement)

References 73 publications

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“…The modification of the cellular lipid content by MK-8722 treatment might also block the release of pro-inflammatory molecules otherwise induced by infection, such as IL-6 and LTB4 12,52 . SARS-CoV-2 affects also cholesterol metabolism 7,53,54 and patients under statins who contracted SARS-CoV-2 developed better T cell responses and showed lower grade of pulmonary symptoms 55,56 . AMPK activation also inhibits HMG-CoA-reductase, the major enzyme for cholesterol synthesis.…”

Section: Discussionmentioning

confidence: 99%

Direct pharmacological AMPK activation inhibits mucosal SARS-CoV-2 infection by reducing lipid metabolism, restoring autophagy flux and the type I IFN response

Cottignies-Calamarte,

Marteau,

et al. 2024

Preprint

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AMP-activated protein kinase (AMPK) plays a central role in regulating cell energy balance. When activated, AMPK supresses energy-consuming pathways such as lipid and protein synthesis while increasing nutrient availability through the activation of autophagy. These pathways downstream AMPK activation contribute to SARS-CoV-2 infection, which hijacks autophagy and accumulates lipid droplets in viral factories to support viral replication. Here, we assessed the antiviral activity of the direct pan-AMPK allosteric activator MK-8722 in vitro. MK-8722 efficiently inhibited infection of Alpha and Omicron SARS-CoV-2 variants in Vero76 and human bronchial epithelial Calu-3 cells at micromolar concentration. This inhibition relied on restoring the autophagic flux, which redirected newly synthesized viral proteins for degradation, and on a reduction in lipid metabolism, which affected the viral factories. Furthermore, MK-8722 treatment increased the type I interferon (IFN-I) response. Post-infection treatment with MK-8722 was enough to inhibit efficiently viral replication and restore the IFN-I response. Finally, MK-8722 treatment did not alter the SARS-CoV-2-specific CD8+ T cell response mounted upon Spike vaccination. Overall, by activating AMPK, MK-8722 acts as an effective antiviral against SARS-CoV-2 infection, even when applied post-exposure, paving the way for preclinical tests aimed at inhibiting viral replication and improving patients' symptoms.

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Section: Discussionmentioning

confidence: 99%

Direct pharmacological AMPK activation inhibits mucosal SARS-CoV-2 infection by reducing lipid metabolism, restoring autophagy flux and the type I IFN response

Cottignies-Calamarte,

Marteau,

et al. 2024

Preprint

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AP3B1 facilitates PDIA3/ERP57 function to regulate rabies virus glycoprotein selective degradation and viral entry

Zhang,

Yang

et al. 2024

Autophagy

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Biological Mechanisms of Aflatoxin B1-Induced Bile Metabolism Abnormalities in Ducklings

Chu,

Yu,

Wang

et al. 2024

Animals

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This study investigated the effects and biological mechanisms of aflatoxin B1 (AFB1) on the health and bile metabolism of ducklings. Forty-eight 1-day-old ducklings were randomly assigned to two groups, with six replicates per group. The control group was fed a basic diet, while the AFB1 group received a diet containing 90 µg/kg of AFB1. The experiment lasted for 2 weeks. The results showed that 90 µg/kg AFB1 caused abnormal bile metabolism; damaged liver cell nuclei and mitochondria; and significantly decreased body weight, average daily weight gain, and levels of albumin, total protein, cholesterol, total superoxide dismutase, glutathione peroxidase, and glutathione. It also significantly increased feed conversion efficiency, along with alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bile acids, and malondialdehyde levels. In the liver, the expression levels of CYP7A1, SCD, and other genes were significantly upregulated, while BSEP, FASN, HMGCR, CAT, and other genes were significantly downregulated. In conclusion, AFB1 causes abnormal bile metabolism and impairs the overall health and liver function of ducklings. Its mechanism of action may involve changes in gene expression related to bile acid metabolism, lipid metabolism, oxidative damage, and cancer pathways.

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The CH24H metabolite, 24HC, blocks viral entry by disrupting intracellular cholesterol homeostasis

Cited by 3 publications

References 73 publications

Direct pharmacological AMPK activation inhibits mucosal SARS-CoV-2 infection by reducing lipid metabolism, restoring autophagy flux and the type I IFN response

Direct pharmacological AMPK activation inhibits mucosal SARS-CoV-2 infection by reducing lipid metabolism, restoring autophagy flux and the type I IFN response

AP3B1 facilitates PDIA3/ERP57 function to regulate rabies virus glycoprotein selective degradation and viral entry

Biological Mechanisms of Aflatoxin B1-Induced Bile Metabolism Abnormalities in Ducklings

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