Figure 6

Schematic model representing MSP as a negative regulator of NASH in hepatocytes and macrophages. Mediators of inflammatory stress—FFA, LPS or oxLDL—induce gene expression of key pro-inflammatory (Tnfα, Il-6 and Mcp-1) and lipogenic (Srebf-1 and Fas) markers in hepatocytes and macrophages, precipitating a pathophysiological condition termed NASH. MSP, a hepatokine and ligand for the RON receptor tyrosine kinase, activates AMPK signaling pathway, in turn stimulating fatty acid oxidation (via the upregulation of Pgc-1α, Cpt-1 and Aco) and inhibiting inflammation and lipogenesis in ex vivo and in vitro models mimicking NASH. AMPK, AMP-activated protein kinase; Aco, acyl-CoA oxidase; Cpt-1, carnitine palmitoyltransferase I; FFA, free fatty acid; IL-6, interleukin 6; LPS, lipopolysaccharide; Mcp-1, monocyte chemoattractant protein-1; MSP, macrophage-stimulating protein; oxLDL, oxidized low-density lipoprotein; Pgc-1α, peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α; RON, recepteur d'origine nantais; TNFα, tumor necrosis factor-α.