TNF drives hepatic APOA-I downregulation during Mycobacterium leprae infection

Leprosy is associated with profound alterations in host lipid metabolism, including high-density lipoprotein (HDL) dysfunction (1, 2). As the liver is the primary site of apolipoprotein A-I (APOA-I) synthesis and HDL biogenesis (3), we investigated whether Mycobacterium leprae infection alters hepatic lipid metabolism and whether inflammatory signaling contributes to these changes. Serum lipid and enzymatic parameters were assessed in patients with leprosy. In vitro, HepG2 cells were exposed to live M. leprae, non-viable bacteria, or PGL-1 (phenolic glycolipid I, a mycobacterial cell wall component). M. leprae infection of HepG2 cells was assessed by immunofluorescence, while APOA1 expression and molecular markers involved in HDL metabolism were evaluated by RT-qPCR, immunoblotting, and ELISA. Our data showed that, patients with multibacillary leprosy exhibited reduced HDL levels, increased triglycerides, and elevated AST compared with paucibacillary patients, indicating systemic lipid alterations associated with disease severity. In vitro, live M. leprae was able to infect HepG2 cells and, unlike non-viable bacteria or mycobacterial components (PGL-1), reduced APOA1 expression and altered the expression of key regulators of HDL biogenesis and clearance. Live M. leprae infection was also associated with increased TNF production. Conditioned medium from infected THP-1-derived macrophages, containing elevated TNF levels, reduced APOA-I expression in HepG2 cells, whereas TNF neutralization and NF-κB inhibition restored APOA1 expression, supporting the involvement of the TNF/NF-κB signaling pathway. Together, our findings identify TNF-driven inflammatory signaling as a potential mechanism linking live M. leprae infection to hepatic APOA-I downregulation and HDL dysfunction, highlighting the liver as an important immunometabolic target in leprosy and providing new insights into the mechanisms underlying disease-associated lipid disturbances.