Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia
Na Zhang, Tingting Geng, Zhangsheng Wang, Ruling Zhang, Tiefeng Cao, Joao Paulo Camporez, Shi-Ying Cai, Ya Liu, Luisa Dandolo, Gerald I. Shulman, Gordon G. Carmichael, Hugh S. Taylor, Yingqun Huang
Na Zhang, Tingting Geng, Zhangsheng Wang, Ruling Zhang, Tiefeng Cao, Joao Paulo Camporez, Shi-Ying Cai, Ya Liu, Luisa Dandolo, Gerald I. Shulman, Gordon G. Carmichael, Hugh S. Taylor, Yingqun Huang
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Research Article Endocrinology Metabolism

Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia

Abstract

Excessive hepatic glucose production (HGP) contributes significantly to the hyperglycemia of type 2 diabetes; however, the molecular mechanism underlying this dysregulation remains poorly understood. Here, we show that fasting temporally increases the expression of H19 long noncoding RNA (lncRNA) in nondiabetic mouse liver, whereas its level is chronically elevated in diet-induced diabetic mice, consistent with the previously reported chronic hepatic H19 increase in diabetic patients. Importantly, liver-specific H19 overexpression promotes HGP, hyperglycemia, and insulin resistance, while H19 depletion enhances insulin-dependent suppression of HGP. Using genome-wide methylation and transcriptome analyses, we demonstrate that H19 knockdown in hepatic cells alters promoter methylation and expression of Hnf4a, a master gluconeogenic transcription factor, and that this regulation is recapitulated in vivo. Our findings offer a mechanistic explanation of lncRNA H19’s role in the pathogenesis of diabetic hyperglycemia and suggest that targeting hepatic H19 may hold the potential of new treatment for this disease.

Authors

Na Zhang, Tingting Geng, Zhangsheng Wang, Ruling Zhang, Tiefeng Cao, Joao Paulo Camporez, Shi-Ying Cai, Ya Liu, Luisa Dandolo, Gerald I. Shulman, Gordon G. Carmichael, Hugh S. Taylor, Yingqun Huang

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Figure 3

Effects of H19 expression on gluconeogenic gene expression and glucose output in vitro.

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Effects of H19 expression on gluconeogenic gene expression and glucose o...
(A) HepG2 cells were transfected with siCon or siH19, followed by RNA extraction and qPCR analysis 48 hours later. Relative RNA levels are presented. (B) HepG2 cells were transfected with siCon or siH19, and glucose output assays were performed 48 hours later. Relative glucose outputs are presented. (C) qPCR results of HepG2 cells transfected with siCon or siH19 at 48-hour time point. (D) HepG2 cells were transfected with siCon or siH19, followed by Western blot analysis 48 hours later. Representative gel images from 3 transfection experiments are shown, with fold decreases in siH19 compared with siCon transfected cells marked on the right. (E–G) Mouse primary hepatocytes were infected with AAV-Vec or AAV-H19 viruses, followed by qPCR and Western blot analyses at 48 hours and glucose output assays at 72 hours. Quantification is based on 3 independent transfection/infection experiments. Numbers are the mean ± SEM. *P < 0.05, **P < 0.01 based on Student t test.