State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
Int J Mol Med. 2014 Jan;33(1):51-8. doi: 10.3892/ijmm.2013.1560. Epub 2013 Nov 19.
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease, characterized by the excess accumulation of lipids in the liver. It has been demonstrated that the dysregulation of lipid droplet (LD)-associated proteins may be involved in the development of NAFLD. Adipose differentiation-related protein (ADRP), as one of the major LD-associated proteins, is expressed in normal and steatotic livers; however, the exact role of ADRP in the liver remains unknown. Previous studies have indicated that metformin, as an antidiabetic drug, effectively ameliorates NAFLD. However, its cellular and molecular mechanisms of action remain to be elucidated. Therefore, the aim of this study was to determine the role of ADRP in the metformin-mediated regulation of hepatic steatosis. We examined the effects of meformin in vivo and in vitro using ob/ob mice and primary hepatocytes, respectively. Lipid accumulation in the hepatocytes was induced by treatment with oleate. Our results revealed that metformin prevented hepatic steatosis in ob/ob mice and inhibited oleate-induced lipid accumulation in primary hepatocytes. Furthermore, using real-time PCR and western blot analysis, we examined the mRNA and protein expression of ADRP, respectively. We found that metformin significantly decreased the expression levels of ADRP. In addition, to further clarify the role of ADRP in lipid accumulation, we generated recombinant adenoviruses to induce the overexpression of ADRP and to knockdown ADRP. In the hepatocytes in which ADRP was overexpressed, the reducing effects of metformin on lipid accumulation were diminished. However, the knockdown of ADRP using siRNA targeting ADRP reduced the accumulation of triglycerides. Taken together, our data demonstrate that metformin prevents hepatic steatosis by regulating the expression of ADRP, which may be a key target in the treatment of NAFLD.
非酒精性脂肪性肝病（NAFLD）是一种常见的肝脏疾病，其特征是肝脏中脂质的过度积累。已经证明，脂滴（LD）相关蛋白的失调可能参与了 NAFLD 的发展。脂肪分化相关蛋白（ADRP）作为主要的 LD 相关蛋白之一，在正常和脂肪变性的肝脏中表达；然而，ADRP 在肝脏中的确切作用尚不清楚。先前的研究表明，二甲双胍作为一种抗糖尿病药物，能有效改善 NAFLD。然而，其细胞和分子作用机制仍有待阐明。因此，本研究旨在确定 ADRP 在二甲双胍介导的肝脂肪变性调节中的作用。我们分别在 ob/ob 小鼠和原代肝细胞中体内和体外研究了二甲双胍的作用。用油酸处理诱导肝细胞内脂质积累。我们的结果表明，二甲双胍可预防 ob/ob 小鼠的肝脂肪变性，并抑制原代肝细胞中油酸诱导的脂质积累。此外，我们通过实时 PCR 和 Western blot 分析分别检测了 ADRP 的 mRNA 和蛋白表达。我们发现二甲双胍显著降低了 ADRP 的表达水平。此外，为了进一步阐明 ADRP 在脂质积累中的作用，我们生成了重组腺病毒来诱导 ADRP 的过表达和敲低 ADRP。在 ADRP 过表达的肝细胞中，二甲双胍对脂质积累的减少作用减弱。然而，用靶向 ADRP 的 siRNA 敲低 ADRP 可减少甘油三酯的积累。总之，我们的数据表明，二甲双胍通过调节 ADRP 的表达来预防肝脂肪变性，ADRP 可能是治疗 NAFLD 的一个关键靶点。
