Very Low-density Lipoprotein-triacylglyceride Promotes Hepatitis B Virus Reactivation

Area of Science:

• Hepatology
• Virology
• Metabolic Diseases

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a complex interaction with chronic hepatitis B virus (CHB) infection.
• MASLD is known to inhibit hepatitis B virus (HBV) replication while concurrently promoting liver fibrosis/cirrhosis (LF/LC).
• A significant gap exists in understanding the mechanistic basis of this paradoxical effect, hindering therapeutic development.

Purpose of the Study:

• To establish and characterize a novel mouse model that recapitulates the interplay between MASLD, CHB infection, and LF/LC.
• To elucidate the role of very low-density lipoprotein (VLDL) and its components in mediating the observed discrepancies in HBV activity and liver pathology.
• To identify potential risk factors and therapeutic targets for managing co-infected patients.

Main Methods:

• Development of a specific HBV-MASLD-LF/LC mouse model to mimic human disease progression.
• Correlation analysis of VLDL-loading triacylglyceride (TAG) levels with HBV titers and LF/LC in both human patients and the mouse model.
• In vitro experiments to assess the causal effect of TAG on HBV titer and fibrotic markers.
• Generation of hepatocyte-specific VLDL receptor knockout (VRKO) mice to investigate VLDL receptor function in this context.

Main Results:

• The established mouse model successfully replicated the promotion of LF/LC and suppression of HBV levels by MASLD.
• VLDL-TAG levels showed a positive correlation with HBV titer and LF/LC in both human cohorts and the mouse model.
• TAG treatment in vitro upregulated HBV titer and fibrotic markers, confirming a causal link.
• VRKO mice exhibited reduced HBV titers but exacerbated LF/LC, with decreased VLDL-TAG levels compared to wild-type controls.
• VLDL levels and VLDL-loading were identified as LF/LC risk factors in a specific CHB patient subgroup.

Conclusions:

• The study provides a physiological explanation for the conflicting effects of MASLD on HBV activity and LF/LC progression.
• VLDL-TAG emerges as a significant factor contributing to the exacerbation of LF/LC and potentially influencing HBV reactivation.
• VLDL-TAG is identified as a novel risk factor for HBV reactivation and warrants further investigation for clinical implications.