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[摘要]：Fetuin-A. a hepatic secretory protein, has recently been implicated in insulin resistance and Type 2 diabetes. It is an endogenous inhibitor of insulin receptor tyrosine kinase. However, regulation of fetuin-A synthesis in relation to insulin resistance is unclear. In the present paper, we report that both non-esterified ('free') fatty acids and fetuin-A coexist at high levels in the serum of db/db mice, indicating an association between them. For an in-depth study, we incubated palmitate with HepG2 cells and rat primary hepatocytes, and found enhanced fetuin-A secretion to more than 4-fold over the control. Interestingly, cell lysates from these incubations showed overexpression and activity of NF-kappa B (nuclear factor kappa B). In NF-kappa B-knockout HepG2 cells, palmitate failed to increase fetuin-A secretion, whereas forced expression of NF-kappa B released fetuin-A massively in the absence of palmitate. Moreover, palmitate stimulated NF-kappa B binding to the fetuin-A promoter resulting in increased reporter activity. These results suggest NF-kappa B to be the mediator of the palmitate effect. Palrnitate-induced robust expression of fetuin-A indicates the occurrence of additional targets, and we found that fetuin-A severely impaired adipocyte function leading to insulin resistance. Our results reveal a new dimension of lipid-induced insulin resistance and open another contemporary target for therapeutic intervention in Type 2 diabetes. |
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