Horii Rika, Honda Masao, Shirasaki Takayoshi, Shimakami Tetsuro, Shimizu Ryogo, Yamanaka Souma, Murai Kazuhisa, Kawaguchi Kazunori, Arai Kuniaki, Yamashita Tatsuya, Sakai Yoshio, Yamashita Taro, Okada Hikari, Nakamura Mikiko, Mizukoshi Eishiro, Kaneko Shuichi
Department of Gastroenterology Kanazawa University Graduate School of Medicine Kanazawa Japan.
Department of Laboratory Medicine Kanazawa University Graduate School of Health Medicine Kanazawa Japan.
Hepatol Commun. 2019 Sep 26;3(12):1687-1703. doi: 10.1002/hep4.1431. eCollection 2019 Dec.
The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up-regulated in advanced chronic hepatitis C (CHC). We found miR-10a regulated various liver metabolism genes and was markedly up-regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR-10a was rhythmic and down-regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 () by directly suppressing the expression of RA receptor-related orphan receptor alpha (). Overexpression of miR-10a in hepatocytes blunted circadian rhythm of and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [], fatty acid synthase [], and ), gluconeogenesis peroxisome proliferator-activated receptor gamma coactivator 1 alpha [], protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of was significantly correlated with the expression of mitochondrial biogenesis-related genes and reduced was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of by miR-10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C-related liver cirrhosis, liver tissue miR-10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C-related hepatocellular carcinoma recurrence. : MiRNA-10a is involved in abnormal liver metabolism in cirrhotic liver through down-regulation of the expression of the circadian rhythm gene Therefore, miR-10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis.
肝脏的昼夜节律在维持其代谢稳态中起着重要作用。我们使用肝脏活检组织的TaqMan聚合酶链反应对微小RNA（miRNA）进行了全面的表达分析，以鉴定在晚期慢性丙型肝炎（CHC）中显著上调的miRNA。我们发现miR-10a调节多种肝脏代谢基因，并且在丙型肝炎病毒感染和营养状况较差的情况下显著上调。miR-10a的表达具有节律性，并通过直接抑制视黄酸受体相关孤儿受体α（）的表达来下调昼夜节律基因脑和肌肉芳烃受体核转运体样蛋白1（）的表达。在肝细胞中过表达miR-10a会减弱的昼夜节律，并抑制脂质合成基因（甾醇调节元件结合蛋白[]、脂肪酸合酶[]和）、糖异生、过氧化物酶体增殖物激活受体γ共激活因子1α[]、蛋白质合成（雷帕霉素哺乳动物靶蛋白[mTOR]和核糖体蛋白S6激酶[S6K]）以及胆汁酸合成（肝脏受体同源物1[LRH1]）的表达。的表达与线粒体生物发生相关基因的表达显著相关，而在CHC中表达降低与血清丙氨酸氨基转移酶水平升高和肝纤维化进展相关。因此，miR-10a对昼夜节律表达的损害会扰乱代谢适应，导致肝损伤，并且与晚期CHC患者肝脏代谢异常的加剧密切相关。在丙型肝炎相关肝硬化患者中，肝脏组织miR-10a水平与肝脏储备、纤维化标志物、食管静脉曲张并发症以及丙型肝炎相关肝细胞癌复发显著相关。：MiRNA-10a通过下调昼夜节律基因的表达参与肝硬化肝脏的异常肝脏代谢。因此，miR-10a是评估肝硬化预后的一种可能有用的生物标志物。
