Liu Meilian, Zhou Lijun, Xu Aimin, Lam Karen S L, Wetzel Michael D, Xiang Ruihua, Zhang Jingjing, Xin Xiaoban, Dong Lily Q, Liu Feng
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18302-7. doi: 10.1073/pnas.0806341105. Epub 2008 Nov 14.
Impairments in adiponectin multimerization lead to defects in adiponectin secretion and function and are associated with diabetes, yet the underlying mechanisms remain largely unknown. We have identified an adiponectin-interacting protein, previously named GST-kappa, by yeast 2-hybrid screening. The adiponectin-interacting protein contains 2 thioredoxin domains and has very little sequence similarity to other GST isoforms. However, this protein shares high sequence and secondary structure homology to bacterial disulfide-bond A oxidoreductase (DsbA) and is thus renamed DsbA-like protein (DsbA-L). DsbA-L is highly expressed in adipose tissue, and its expression level is negatively correlated with obesity in mice and humans. DsbA-L expression in 3T3-L1 adipocytes is stimulated by the insulin sensitizer rosiglitazone and inhibited by the inflammatory cytokine TNFalpha. Overexpression of DsbA-L promoted adiponectin multimerization while suppressing DsbA-L expression by RNAi markedly and selectively reduced adiponectin levels and secretion in 3T3-L1 adipocytes. Our results identify DsbA-L as a key regulator for adiponectin biosynthesis and uncover a potential new target for developing therapeutic drugs for the treatment of insulin resistance and its associated metabolic disorders.
脂联素多聚化受损会导致脂联素分泌和功能缺陷，并与糖尿病相关，但潜在机制仍 largely 未知。我们通过酵母双杂交筛选鉴定出一种与脂联素相互作用的蛋白，先前命名为 GST-κ。该与脂联素相互作用的蛋白含有 2 个硫氧还蛋白结构域，与其他 GST 同工型的序列相似性很小。然而，这种蛋白与细菌二硫键 A 氧化还原酶（DsbA）具有高度的序列和二级结构同源性，因此重新命名为类 DsbA 蛋白（DsbA-L）。DsbA-L 在脂肪组织中高度表达，其表达水平在小鼠和人类中与肥胖呈负相关。3T3-L1 脂肪细胞中 DsbA-L 的表达受胰岛素增敏剂罗格列酮刺激，并受炎性细胞因子 TNFα 抑制。DsbA-L 的过表达促进脂联素多聚化，而通过 RNAi 抑制 DsbA-L 的表达则显著且选择性地降低 3T3-L1 脂肪细胞中脂联素的水平和分泌。我们的结果确定 DsbA-L 是脂联素生物合成的关键调节因子，并揭示了一个开发治疗胰岛素抵抗及其相关代谢紊乱治疗药物的潜在新靶点。
