Regulation of LECT2 expression via TLR4 in response to LPS stimulation in hepatocytes

Abstract

Leukocyte cell-derived chemotaxin 2 (LECT2), a secreted protein, is implicated in various physiological and pathological processes. As a hepatokine, LECT2 is predominantly synthesized and secreted by hepatocytes, with elevated levels being associated with multiple human inflammatory diseases. Although LECT2 plays a critical role in liver and systemic inflammation, the intracellular signaling mechanisms governing its expression under inflammatory conditions remain unclear. This study demonstrates that lipopolysaccharide (LPS) directly induces LECT2 expression in AML12 mouse hepatocytes. Use of a TLR4-specific inhibitor confirmed that LPS-induced LECT2 expression is mediated via its canonical receptor, TLR4. Furthermore, the p38 MAPK pathway was identified as a key mediator of this response, as evidenced by pharmacological modulation with a p38-specific inhibitor and agonist. Promoter analysis of the Lect2 gene revealed the presence of a putative AP−1-like binding site, suggesting transcriptional regulation by AP−1. Overexpression of c–Fos and c–Jun, along with ChIP–qPCR analysis, confirmed that AP−1 directly binds to Lect2 promoter, and regulates its transcription in response to LPS. Together, these findings reveal a novel TLR4/p38 MAPK/AP−1 signaling axis that, during inflammation, regulates LECT2 expression in hepatocytes, providing new insights into the molecular mechanisms underlying liver inflammation and LECT2-mediated pathophysiology.