Inhibition of LPCAT3 exacerbates endoplasmic reticulum stress and HBV replication

BACKGROUND: Altered phospholipid metabolism plays a key role in changing the immune microenvironment and severely affecting T-cell function. LPCAT3 is one of the vital enzymes regulating phospholipid metabolism. This study aims to verify the effect of LPCAT3 on HBV replication in vitro and the chronic progression of hepatitis B infection based on the results of lipidomic. METHODS: Untargeted lipidomic analysis was employed to scrutinize discrepancies in lipid metabolites between 40 HBV-infected patients and those who spontaneously cleared the virus. Subsequently, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot assay (ELISPOT), western blotting (WB) and quantitative polymerase chain reaction (qPCR) were utilized to investigate LPCAT3 expression and assess HBV replication and endoplasmic reticulum stress (ERS). RESULTS: A comparative analysis between HBV-infected patients and those experiencing spontaneous clearance revealed significant disparities in 24 lipid metabolites. Among these, phosphatidylcholine (PC) and lysophosphatidylcholine (LPC), constituting half (12/24) of the identified metabolites, were identified as substrates and products of LPCAT3. In vitro studies demonstrated that inhibiting LPCAT3 led to elevated expression levels of hepatitis B surface antigen (HBsAg), HBV-DNA, and interferon-γ (IFN-γ) (P < 0.05), indicative of heightened HBV replication. Furthermore, LPCAT3 inhibition significantly upregulated the expression of genes associated with ERS (P < 0.05). CONCLUSIONS: Inhibiting LPCAT3 significantly correlates with HBV replication and induces inflammation by enhancing ERS. We hypothesize that LPCAT3 serves as a potential biomarker for hepatitis B virus replication and chronic progression. Furthermore, these findings elucidate the malignant progression of HBV infection from the standpoint of lipid metabolism, offering a novel insight for subsequent mechanistic exploration or therapeutic studies. LAY SUMMARY: LPCAT3 inhibition enhances endoplasmic reticulum stress and HBV replication by altering the membrane phospholipid composition and promotes chronic hepatitis B progression.