Dyslipidemia and insulin resistance in obesity can lead to lipotoxicity and cellular damage. Renal lipotoxicity in association with an impairment of lipid metabolism induces renal damage through the activation of inflammation, ER stress, fibrosis and apoptosis. We investigated the effects of a combination treatment of the DPP-4 inhibitor vildagliptin and atorvastatin on renal lipotoxicity related to renal dysfunction and injury in a high-fat high-fructose diet (HFF)-induced insulin resistant condition. Male Wistar rats were fed on a high-fat diet and were given drinking water with 10% fructose for 16 weeks. After that, rats were divided into: no treatment (HFF), treatment with vildagliptin, atorvastatin and vildagliptin plus atorvastatin for 4 weeks. The results demonstrated that the combination treatment prominently improved insulin resistance, dyslipidemia and kidney morphological changes induced by HFF. These changes correlated well with the increased expression of nephrin and podocin and decreased urine protein. Notably, the combined treatment produced greater improvement in renal lipid metabolism through increasing fatty acid oxidation with the decreases in fatty acid transporters and fatty acid synthesis, thereby reducing renal lipid accumulation in HFF rats. The reduction in renal lipotoxicity via diminishing renal inflammation, ER stress, fibrosis and apoptosis was also more significant in the combined treatment group than in the other groups in which the drug was used as a monotherapy. In conclusion, the combination therapy produced synergistic beneficial effects on metabolic parameters, lipid metabolism and accumulation related to renal lipid accumulation-induced lipotoxicity and kidney injury in the HFF-induced insulin resistant model with improved outcomes.

肥胖中的血脂异常和胰岛素抵抗可导致脂质毒性和细胞损伤。肾脂质毒性与脂质代谢受损相关，通过炎症，内质网应激，纤维化和细胞凋亡的激活而引起肾脏损害。我们研究了在高脂高果糖饮食（HFF）诱导的胰岛素抵抗条件下，DPP-4抑制剂维达列汀和阿托伐他汀联合治疗对与肾功能不全和损伤相关的肾脏脂质毒性的影响。以高脂饮食喂养雄性Wistar大鼠，并给予其含10％果糖的饮用水16周。之后，将大鼠分为：不治疗（HFF），用维达列汀，阿托伐他汀和维达列汀加阿托伐他汀治疗4周。结果表明，联合治疗显着改善了胰岛素抵抗，HFF引起的血脂异常和肾脏形态变化。这些变化与nephrin和podocin表达的增加以及尿蛋白的减少密切相关。值得注意的是，联合治疗通过增加脂肪酸氧化，减少脂肪酸转运蛋白和脂肪酸合成，在肾脂质代谢方面产生了更大的改善，从而减少了HFF大鼠的肾脏脂质积聚。在联合治疗组中，通过减少肾脏炎症，内质网应激，纤维化和细胞凋亡而减少的肾脏脂毒性也比将药物用作单一疗法的其他组更为显着。总之，联合疗法对代谢参数产生了协同有益的作用，