Alteration of glycosphingolipid (GSL) expression plays key roles in the pathogenesis and pathophysiology of many important human diseases, including cancer, diabetes and glycosphingolipidosis. Inflammatory processes are involved in development and progression of diabetic nephropathy, a major complication of type 2 diabetes mellitus. GSLs are known to play roles in inflammatory responses in various diseases, and levels of renal GSLs are elevated in mouse models of diabetic nephropathy; however, little is known regarding the pathophysiological role of these GSLs in this disease process. We studied proinflammatory activity of GSLs in diabetic nephropathy using spontaneously diabetic mouse strain KK. Mice were fed a high-fat diet (HFD) (60% kcal from fat) or normal diet (ND) (4.6% kcal from fat) for a period of 8 wk. HFD-feeding resulted in quantitative and qualitative changes of renal globo-series GSLs (particularly Gb3Cer), upregulation of TNF-α, and induction of renal inflammation. Gb3Cer/Gb4Cer treatment enhanced inflammatory responses via TLR4 in TLR4/MD-2 complex expressing cells, including HEK293T, mouse bone marrow-derived macrophages (BMDMs) and human monocytes. Our findings suggest that HFD-induced increase of Gb3Cer/Gb4Cer positively modulate TLR4-mediated inflammatory response, and that such GSLs play an important pathophysiological role in diabetic nephropathy.

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Globo系列糖鞘脂可增强Toll样受体4介导的炎症，并在糖尿病性肾病中发挥病理生理作用

糖鞘脂（GSL）表达的改变在许多重要的人类疾病（包括癌症，糖尿病和糖鞘脂病）的发病机理和病理生理中起着关键作用。炎症过程与糖尿病性肾病的发展和进展有关，糖尿病性肾病是2型糖尿病的主要并发症。已知GSL在多种疾病的炎症反应中起作用，并且在糖尿病性肾病的小鼠模型中肾GSL的水平升高。然而，关于这些GSL在该疾病过程中的病理生理作用还知之甚少。我们研究了自发性糖尿病小鼠品系KK在糖尿病性肾病中GSL的促炎活性。给小鼠喂食高脂饮食（HFD）（脂肪含量为60％大卡）或普通饮食（ND）（脂肪含量为4.6％大卡），为期8周。HFD喂养导致肾脏球系列GSL（尤其是Gb3Cer）发生定量和定性变化，TNF-α上调，并诱发肾脏炎症。Gb3Cer / Gb4Cer处理可在TLR4 / MD-2复合物表达细胞（包括HEK293T，小鼠骨髓衍生的巨噬细胞（BMDM）和人单核细胞）中通过TLR4增强炎症反应。我们的发现表明，HFD诱导的Gb3Cer / Gb4Cer的增加正调控TLR4介导的炎症反应，并且此类GSL在糖尿病性肾病中起重要的病理生理作用。小鼠骨髓来源的巨噬细胞（BMDM）和人单核细胞。我们的发现表明，HFD诱导的Gb3Cer / Gb4Cer的增加正调控TLR4介导的炎症反应，并且此类GSL在糖尿病性肾病中起重要的病理生理作用。小鼠骨髓来源的巨噬细胞（BMDM）和人单核细胞。我们的发现表明，HFD诱导的Gb3Cer / Gb4Cer的增加正调控TLR4介导的炎症反应，并且此类GSL在糖尿病性肾病中起重要的病理生理作用。