Lipase inhibitor orlistat prevents hepatitis B virus infection by targeting an early step in the virus life cycle

Abstract

Hepatitis B Virus (HBV) is a strictly hepatotropic pathogen which is very efficiently targeted to the liver and into its host cell, the hepatocyte. The sodium taurocholate co-transporting polypeptide (NTCP) has been identified as a key virus entry receptor, but the early steps in the virus life cycle are still only barely understood. Here, we investigated the effect of lipase inhibition and lipoprotein uptake on HBV infection using differentiated HepaRG cells and primary human hepatocytes. We found that an excess of triglyceride rich lipoprotein particles in vitro diminished HBV infection and a reduced hepatic virus uptake in vivo if apolipoprotein E is lacking indicating virus transport along with lipoproteins to target hepatocytes. Moreover, we showed that HBV infection of hepatocytes was inhibited by the broadly active lipase inhibitor orlistat, approved as a therapeutic agent which blocks neutral lipid hydrolysis activity. Orlistat treatment targets HBV infection at a post-entry step and inhibited HBV infection during virus inoculation strongly in a dose-dependent manner. In contrast, orlistat had no effect on HBV gene expression or replication or when added after HBV infection. Taken together, our data indicate that HBV connects to the hepatotropic lipoprotein metabolism and that inhibition of cellular hepatic lipase(s) may allow to target early steps of HBV infection.

The Fatty Acid Lipid Metabolism Nexus in COVID-19

“…In other viral settings, orlistat and metformin were shown to inhibit replication of several flaviviruses [109][110][111][112], as well as hepatitis B virus and HCV [113][114][115][116][117], coxsackievirus B3 and varicella-zoster virus [118,119]. For these viruses, orlistat was shown to inhibit lipid-vesicle restructuring, viral genome replication, virion protein palmitoylation [109][110][111]118] and virus entry [113,114]. Metformin was shown to decrease lipid (palmitate) synthesis [119], viral RNA transcription and protein synthesis [115,116], as well as virus-dependent glycolysis, while increasing IFN production and blocking inflammatory cytokines [112,117].…”

Liver macrophages: Friend or foe during hepatitis B infection?

“…Among the mediators inhibiting HBV infection, IFN‐α and IFN‐γ were identified and shown to directly inhibit HBV replication in patients . Moreover, a recent study showed that HBV virions hijack enzymes involved in lipid metabolism to infect hepatocytes . It could be hypothesized that the same pathways could be also hijacked by HBV in MΦ to enter or pass through these cells to be delivered to hepatocytes.…”

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

“…Inhibition of these enzymes inhibits HCV and rotavirus replication. More general inhibitors of fatty acid synthetase such as Orlistat, also decrease replication of several different viruses [17][18][19][20] .…”