Danielli Mauro, Capiglioni Alejo M, Marrone Julieta, Calamita Giuseppe, Marinelli Raúl A
Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari "Aldo Moro,", Bari, Italy.
IUBMB Life. 2017 May;69(5):341-346. doi: 10.1002/iub.1615. Epub 2017 Mar 20.
Hepatocyte mitochondrial aquaporin-8 (mtAQP8) works as a multifunctional membrane channel protein that facilitates the uptake of ammonia for its detoxification to urea as well as the mitochondrial release of hydrogen peroxide. Since early oligonucleotide microarray studies in liver of cholesterol-fed mice showed an AQP8 downregulation, we tested whether alterations of cholesterol content per se modulate mtAQP8 expression in human hepatocyte-derived Huh-7 cells. Cholesterol loading with methyl-β-cyclodextrin (mβCD):cholesterol complexes downregulated the proteolytic activation of cholesterol-responsive sterol regulatory element-binding protein (SREBP) transcriptions factors 1 and 2, and the expression of the target gene 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Under such conditions, mtAQP8 mRNA and protein expressions were significantly reduced. In contrast, cholesterol depletion using mβCD alone increased SREBP-1 and 2 activation and upregulated HMGCR and mtAQP8 mRNA and protein expressions. The results suggest that cholesterol can regulate transcriptionally human hepatocyte mtAQP8 expression likely via SREBPs. The functional implications of our findings are discussed. © 2017 IUBMB Life, 69(5):341-346, 2017.
肝细胞线粒体水通道蛋白8（mtAQP8）作为一种多功能膜通道蛋白，可促进氨的摄取以将其解毒为尿素，以及促进过氧化氢的线粒体释放。由于早期对喂食胆固醇的小鼠肝脏进行的寡核苷酸微阵列研究显示AQP8表达下调，我们测试了胆固醇含量的改变本身是否会调节人肝细胞来源的Huh-7细胞中mtAQP8的表达。用甲基-β-环糊精（mβCD）：胆固醇复合物加载胆固醇可下调胆固醇反应性固醇调节元件结合蛋白（SREBP）转录因子1和2的蛋白水解激活以及靶基因3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的表达。在这种情况下，mtAQP8 mRNA和蛋白表达显著降低。相反，单独使用mβCD消耗胆固醇会增加SREBP-1和2的激活，并上调HMGCR以及mtAQP8 mRNA和蛋白的表达。结果表明，胆固醇可能通过SREBPs转录调节人肝细胞mtAQP8的表达。我们讨论了这些发现的功能意义。©2017国际生物化学与分子生物学联盟生命科学，69(5):341 - 346，2017。
