Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
Free Radic Biol Med. 2019 Feb 1;131:370-375. doi: 10.1016/j.freeradbiomed.2018.12.016. Epub 2018 Dec 21.
Cholesterol, via sterol regulatory element-binding protein (SREBP) transcription factors, activates or represses genes involved in its hepatic biosynthetic pathway, and also modulates the expression of hepatocyte mitochondrial aquaporin-8 (mtAQP8), a channel that can function as peroxiporin by facilitating the transmembrane diffusion of HO. Here we tested the hypothesis that mtAQP8 is involved in the SREBP-mediated regulation of hepatocyte cholesterol biosynthesis. Using human hepatocyte-derived Huh-7 cells and primary rat hepatocytes, we found that mtAQP8 knockdown significantly downregulated de novo cholesterol synthesis as well as protein expressions of SREBP-2 and its target gene, a rate-limiting enzyme in cholesterol synthesis 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR). In contrast, adenovirus-mediated human AQP8 mitochondrial expression significantly increased de novo cholesterol synthesis and protein expressions of SREBP-2 and HMGCR. In mtAQP8-overexpressed hepatocytes, mitochondrial HO release was found to be increased; and a mitochondria-targeted antioxidant prevented the upregulation of mitochondrial HO release and that of cholesterol synthesis. Our results suggest that peroxiporin mtAQP8 plays a role in the SREBP-controlled hepatocyte cholesterogenesis, a finding that might be relevant to cholesterol-related metabolic disorders.
胆固醇通过固醇调节元件结合蛋白（SREBP）转录因子激活或抑制其肝脏生物合成途径中涉及的基因，并调节肝细胞线粒体水通道蛋白-8（mtAQP8）的表达，该通道可作为过氧化物酶体通过促进 HO 的跨膜扩散而起作用。在这里，我们测试了 mtAQP8 是否参与 SREBP 介导的肝细胞胆固醇生物合成调节的假设。使用人源性肝细胞衍生的 Huh-7 细胞和原代大鼠肝细胞，我们发现 mtAQP8 敲低显著下调了从头胆固醇合成以及 SREBP-2 及其靶基因胆固醇合成限速酶 3-羟基-3-甲基戊二酰基辅酶 A 还原酶（HMGCR）的蛋白表达。相比之下，腺病毒介导的人 AQP8 线粒体表达显著增加了从头胆固醇合成和 SREBP-2 和 HMGCR 的蛋白表达。在 mtAQP8 过表达的肝细胞中，发现线粒体 HO 释放增加；并且线粒体靶向抗氧化剂可防止线粒体 HO 释放和胆固醇合成的上调。我们的结果表明，过氧化物酶体 mtAQP8 在 SREBP 控制的肝细胞胆固醇生成中起作用，这一发现可能与胆固醇相关的代谢紊乱有关。
