LPS stimulation-induced regulation of LECT2 expression via TLR4 in hepatocytes
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Leukocyte cell-derived chemotaxin 2 (LECT2), a secreted protein,is implicated in various physiological and pathologicalprocesses. As a hepatokine, LECT2 is predominantly synthesizedand secreted by hepatocytes, with elevated levels beingassociated with multiple human inflammatory diseases. AlthoughLECT2 plays a critical role in liver and systemic inflammation,the intracellular signaling mechanisms governing its expressionunder inflammatory conditions remain unclear. This studydemonstrates that lipopolysaccharide (LPS) directly inducesLECT2 expression in AML12 mouse hepatocytes. Use of aTLR4-specific inhibitor confirmed that LPS-induced LECT2 expressionis mediated via its canonical receptor, TLR4. Furthermore,the p38 MAPK pathway was identified as a key mediatorof this response, as evidenced by pharmacological modulationwith a p38-specific inhibitor and agonist. Promoter analysis ofthe Lect2 gene revealed the presence of a putative AP−1-likebinding site, suggesting transcriptional regulation by AP−1. Overexpression of c–Fos and c–Jun, along with ChIP–qPCRanalysis, 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−1signaling axis that, during inflammation, regulates LECT2 expressionin hepatocytes, providing new insights into the molecularmechanisms underlying liver inflammation and LECT2-mediatedpathophysiology.
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2), a secreted protein,is implicated in various physiological and pathologicalprocesses. As a hepatokine, LECT2 is predominantly synthesizedand secreted by hepatocytes, with elevated levels beingassociated with multiple human inflammatory diseases. AlthoughLECT2 plays a critical role in liver and systemic inflammation,the intracellular signaling mechanisms governing its expressionunder inflammatory conditions remain unclear. This studydemonstrates that lipopolysaccharide (LPS) directly inducesLECT2 expression in AML12 mouse hepatocytes. Use of aTLR4-specific inhibitor confirmed that LPS-induced LECT2 expressionis mediated via its canonical receptor, TLR4. Furthermore,the p38 MAPK pathway was identified as a key mediatorof this response, as evidenced by pharmacological modulationwith a p38-specific inhibitor and agonist. Promoter analysis ofthe Lect2 gene revealed the presence of a putative AP−1-likebinding site, suggesting transcriptional regulation by AP−1. Overexpression of c–Fos and c–Jun, along with ChIP–qPCRanalysis, 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−1signaling axis that, during inflammation, regulates LECT2 expressionin hepatocytes, providing new insights into the molecularmechanisms underlying liver inflammation and LECT2-mediatedpathophysiology.