Fetuin A ELISA Kit, Antibody, Protein

Alternative name(s):

• Alpha-2-HS-glycoprotein
• Ba-alpha-2-glycoprotein
• Alpha-2-Z-globulin
• AHSG

Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance

Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.

Pal D et al. Nat Med. 2012 Jul 29. doi: 10.1038/nm.2851. [Epub ahead of print]

Plasma Levels of Fetuin-A and Hepatic Enzymes and Risk of Type 2 Diabetes in Women in the U.S

Fetuin-A interferes with insulin action in animal studies, but data on fetuin-A and diabetes risk in humans are sparse and the role of nonalcoholic fatty liver disease in this association is unknown. From 2000 to 2006, we prospectively identified 470 matched incident diabetes case-control pairs in the Nurses' Health Study, for whom levels of plasma fetuin-A, alanine transaminase (ALT), and γ-glutamyltranspeptidase (GGT) were measured. After multivariate adjustment for covariates, including ALT and GGT, the odds ratio (OR) (95% confidence interval [CI]) comparing extreme fetuin-A quintiles was 1.81 (1.07-3.06) (P for trend = 0.009). A mediational analysis showed that this positive association was largely (79.9%) explained by fasting insulin and hemoglobin A(1c) levels; after further adjustment of these factors, the OR (95% CI) comparing extreme quintiles was attenuated to 1.09 (0.56-2.10) (P for trend = 0.42). In addition, liver enzymes did not modify this association (P for interaction = 0.91 for ALT and 0.58 for GGT). When results from this study were pooled with those in three prior prospective investigations of the same association, a consistent, positive association was observed between high fetuin-A levels and diabetes risk: the relative risk (95% CI) comparing high versus low fetuin-A levels was 1.69 (1.39-2.05) (P for heterogeneity = 0.45). These findings suggest that plasma fetuin-A levels were independently associated with higher risk of developing type 2 diabetes.

Sun Q , et al. Diabetes. 2012 Aug 24. [Epub ahead of print]