Lipid homeostasis and mevalonate pathway in COVID-19: Basic concepts and potential therapeutic targets

Abstract

Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic. Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection. In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality. Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected.

Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study

“…COVID-19 pandemic has driven a number of studies of drug repurposing ( Fajgenbaum and Rader, 2020 ; Gaziano et al, 2021 ). The role of lipid metabolism in viral infections has raised interest regarding the possibility of repurposing lipid-lowering drugs as anti-COVID-19 agents ( Proto et al, 2021 ). As one of the most commonly prescribed drugs, statins have received the greatest attention for their pleiotropic effects, including lowering serum cholesterol, anti-inflammatory and immunomodulatory properties, and antithrombotic effect, all of which play a role in viral infections ( Fajgenbaum and Rader, 2020 ; Proto et al, 2021 ; Rubin, 2021 ).…”

“…Available studies have suggested an important role of lipid metabolism in viral infections, including in the pathogenesis of SARS-CoV-2 infection (Proto et al, 2021).…”

“…The plausible mechanisms include the involvement of host lipids in the virus life cycle, the influence of cholesterol on the immune cell functions, interfering with the mevalonate pathway, and so on (Proto et al, 2021). Such evidence indicates the potential protective effect of lipid-lowering drugs against COVID-19.…”

“…Available studies have suggested an important role of lipid metabolism in viral infections, including in the pathogenesis of SARS-CoV-2 infection ( Proto et al, 2021 ). The plausible mechanisms include the involvement of host lipids in the virus life cycle, the influence of cholesterol on the immune cell functions, interfering with the mevalonate pathway, and so on Proto et al, 2021 . Such evidence indicates the potential protective effect of lipid-lowering drugs against COVID-19.…”

Possible Targets of Pan-Coronavirus Antiviral Strategies for Emerging or Re-Emerging Coronaviruses

“…Further analysis showed that the regulators of cholesterol homeostasis, including sterol regulatory element-binding protein 2(SREBP 2), SREBP cleavage-activating protein (SCAP), membrane-bound transcription factor site 1 protease (MBTPS1), MBTPS2, Niemann–Pick intracellular cholesterol transporter 2 (NPC2), and secretion associated ras-related GTPase 1A (SAR1A), play key roles in coronaviruses’ infection [ 56 , 74 ]. Moreover, coronaviruses require cholesterol, for viral entry, pathological syncytia formation, and pathogenesis [ 58 , 59 , 60 ], and 25-hydrocholesterol (25HC), which is converted from cholesterol by cholesterol 25-hydroxylase (CH25H), broadly inhibits the virus-cell membrane fusion of human coronaviruses by depleting membrane cholesterol [ 61 , 62 ]. Therefore, targeting the key host factors of lipid metabolism, which involve membrane fusion, endolysosomal acidification, and cholesterol accumulation (such as SCAP, TMEM41B), may be a potential therapeutic strategy for pan-coronavirus.…”