Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, United States.
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, United States.
Biochem Biophys Res Commun. 2014 Jul 25;450(2):1027-31. doi: 10.1016/j.bbrc.2014.06.095. Epub 2014 Jun 26.
Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na(+)/H(+) exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.
非酒精性脂肪性肝病 (NAFLD) 与脂质动态平衡失调密切相关。饮食诱导的肝脂肪变性可引发 NAFLD 进展，研究表明缺乏电中性 Na(+)/H(+)交换蛋白 NHE1 (Slc9a1) 的小鼠中肝脂肪变性显著减少。在这项研究中，我们研究了 NHE1 缺乏是否会对肝脏产生影响，从而有助于对异常脂质积累的明显保护作用。对野生型和 NHE1 敲除型肝脏的 RT-PCR 和免疫印迹分析显示，表达谱强烈表明从头合成脂质和肝星状细胞激活均受到抑制，这与肝纤维化有关。这包括法尼醇 X 受体 FXR、过氧化物酶体增殖物激活受体 PPARγ、其共激活因子 PGC1α 和参与肝代谢稳态的抗氧化蛋白 sestrin 2 的上调。此外，促脂性肝 X 受体 LXRα 和乙酰辅酶 A 羧化酶 1 和 2 的表达水平下调。这些变化与细胞应激减少有关，即使在高脂肪饮食暴露下，这种应激也持续存在，胰岛素信号的保存更好，如蛋白激酶 B/Akt 磷酸化 (Ser473) 所示。这些结果表明，NHE1 缺乏可能会预防 NAFLD 发病机制，鉴于存在高度特异性的 NHE1 抑制剂，这一点意义重大。
