Abstract
Macrophage stimulating protein (MSP) is a multifunctional serum protein produced in the liver, belonging to the plasminogen-related kringle protein family. It exerts diverse biological functions by activating a transmembrane receptor protein-tyrosine kinase known as RON in humans and SKT in mice. MSP plays a pivotal role in innate immunity and is involved in various activities such as cell survival, migration, and phagocytosis. Elucidating the regulatory mechanisms governing MSP gene expression is of great importance. In this study, we comprehensively elucidate the molecular mechanism underlying hepatic MSP gene expression in response to alcoholism. Exposure to ethanol specifically upregulated the expression of ERRγ and MSP in the liver, while not in other organs. Liver-specific knockout of the cannabinoid receptor type 1 (CB1R), an upstream regulator of ERRγ, inhibited the alcohol-induced upregulation of MSP expression. Overexpression of ERRγ alone was sufficient to enhance MSP expression in hepatic cell lines and in mice. Conversely, knockdown of ERRγ in cell lines or liver-specific knockout of ERRγ in mice reversed ethanol-induced MSP gene expression. Promoter studies revealed the direct binding of ERRγ to the MSP gene promoter at the ERR response element (ERRE), resulting in the positive regulation of MSP gene expression in response to alcohol. This finding was further supported by ERRE-mutated MSP-luciferase reporter assays. Notably, treatment with GSK5182, an ERRγ-specific inverse agonist, significantly suppressed alcohol-induced hepatic MSP expression. Collectively, we exposed a novel mechanistic understanding of how alcohol-induced ERRγ controls the transcriptional regulation of MSP gene expression in the liver.