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. 2022 Jul 18;10:945287. doi: 10.3389/fcell.2022.945287

FIGURE 2.

FIGURE 2

The putative inflammatory role of fetuin-A. FFA-mediated oversecretion of fetuin-A from the liver, adipocytes, and pancreatic beta cells induces an inflammatory signaling pathways by employing several mechanisms. Fetuin-A acts as a ligand for TLR-4 and a macrophage-polarizing agent that transforms the anti-inflammatory (M2) to the inflammatory (M1) phenotype of macrophages. It also induces an inflammatory process by directly recruiting macrophages (acts as a chemoattractant) and by stimulating MCP1 and iNOS through the JNK-cJun-IFNγ-JAK2-STAT1-NOX4 pathway. Eventually, fetuin-A triggered inflammation leads to NAFLD, ATI, beta cell apoptosis, IR, and hence T2DM. Abbreviations: ATI, Adipose tissue inflammation; FFA, free fatty acid; IFN-γ, interferon-gamma; iNOS, inducible nitric oxide synthase; IR, insulin resistance; JAK 2, Janus kinase; MCP-1, monocyte chemoattractant protein-1; NAFLD, nonalcoholic liver disease; NOX4, NADPH oxidase 4; STAT1, signal transducer and activator of transcription; T2DM, type 2 diabetes mellitus; TLR-4, toll-like receptor-4.