Targeting lipid biosynthesis pathways for hepatitis B virus cure

Area of Science:

• Hepatology
• Virology
• Metabolic pathways

Background:

• Chronic hepatitis B virus (HBV) infection is linked to high levels of non-infectious HBV surface antigen (HBsAg) particles.
• Elevated HBsAg is associated with chronic immune dysfunction in patients.

Purpose of the Study:

• To investigate the role of lipid metabolism in HBV infection.
• To evaluate the efficacy of targeting lipid metabolic pathways for HBsAg reduction.

Main Methods:

• Lipid and metabolomic analysis in humanized immunodeficient chimeric mouse livers.
• In vitro studies using HepG2-NTCP cells infected with HBV.
• Treatment with small molecule inhibitors targeting lipid biosynthetic enzymes (ACC, fatty acid synthase, SKI-1/S1P).
• In vivo studies using HBV-infected liver chimeric mice treated with a liver-targeted ACC inhibitor.

Main Results:

• HBV infection dysregulates multiple lipid metabolic pathways.
• Inhibitors of ACC, fatty acid synthase, and SKI-1/S1P potently reduced extracellular HBsAg in vitro.
• A liver-targeted ACC inhibitor showed no antiviral activity in vivo, despite on-target engagement.
• In vitro HBsAg production appears dependent on hepatic de novo lipogenesis, but this can be bypassed in vivo.

Conclusions:

• Hepatic de novo lipogenesis contributes to HBsAg production in vitro.
• Extrahepatic lipid sources (lipolysis, diet) can compensate for hepatic inhibition in vivo.
• Combination therapies targeting multiple lipid metabolic pathways may be required to effectively reduce HBsAg in chronic HBV infection.