1. Up-regulation of selenoprotein P and HIP/PAP mRNAs in hepatocytes by intermittent hypoxia via down-regulation of miR-203
- Author
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Ryogo Shobatake, Shin Takasawa, Sumiyo Sakuramoto-Tsuchida, Tomoko Uchiyama, Mai Makino, Maiko Takeda, Asako Itaya-Hironaka, Chiho Ohbayashi, Hiroyo Ota, Hiroshi Kimura, and Akiyo Yamauchi
- Subjects
0301 basic medicine ,FGF21 ,FGF21, fibroblast growth factor 21 ,WST-8, 2-(2-methoxy-4-nitrophenyl)−3-(4-nitrophenyl)−5-(2,4-disulfophenyl)−2H-tetrazolium monosodium salt ,Biochemistry ,miRNA, micro RNA ,0302 clinical medicine ,HIP/PAP ,lcsh:QD415-436 ,ANGPTL6, angiopoietin-related growth factor ,lcsh:QH301-705.5 ,RpS15, ribosomal protein S15 ,Reg, regenerating gene ,Selenoprotein P ,SHBG, sex hormone-binding globulin ,Intermittent hypoxia ,ELISA, enzyme-linked immunosorbent assay ,miR-203 ,IH, intermittent hypoxia ,Reverse transcription polymerase chain reaction ,AHSG, α2 HS-glycoprotein ,030220 oncology & carcinogenesis ,SELENOP, selenoprotein P ,Research Article ,Hepatokine ,Biophysics ,LECT2, leukocyte cell-derived chemotaxin 2 ,Biology ,lcsh:Biochemistry ,03 medical and health sciences ,Insulin resistance ,Downregulation and upregulation ,microRNA ,medicine ,HIP/PAP, hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein ,SELENOP ,Rig, rat insulinoma gene ,MCPIP1, monocyte chemotactic protein-induced protein 1 ,medicine.disease ,Molecular biology ,030104 developmental biology ,TP63, transformation-related protein 63 ,lcsh:Biology (General) ,siRNA, small interfering RNA ,DROSHA, ribonuclease type III ,SAS, sleep apnea syndrome ,REG family gene ,DICER, endoribonuclease Dicer ,FCS, fetal calf serum - Abstract
Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human hepatocytes (JHH5, JHH7, and HepG2) to experimental IH or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction (RT-PCR), and found that IH significantly increased the mRNA levels of selenoprotein P (SELENOP) — a hepatokine — and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) — one of REG (Regenerating gene) family. We next investigated promoter activities of both genes and discovered that they were not increased by IH. On the other hand, a target mRNA search of micro RNA (miRNA) revealed that both mRNAs have a potential target sequence for miR-203. The miR-203 level of IH-treated cells was significantly lower than that of normoxia-treated cells. Thus, we introduced miR-203 inhibitor and a non-specific control RNA (miR-203 inhibitor NC) into HepG2 cells and measured the mRNA levels of SELENOP and HIP/PAP. The IH-induced expression of SELENOP and HIP/PAP was abolished by the introduction of miR-203 inhibitor but not by miR-203 inhibitor NC. These results demonstrate that IH stress up-regulates the levels of SELENOP in human hepatocytes to accelerate insulin resistance and up-regulates the levels of HIP/PAP mRNAs to proliferate such hepatocytes, via the miR-203 mediated mechanism., Graphical abstract fx1
- Published
- 2017