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 6

Effects of H19 expression on hepatic Hnf4a promoter methylation, gluconeogenic gene expression, and insulin signaling in vivo.

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Effects of H19 expression on hepatic Hnf4a promoter methylation, glucone...
Genomic DNAs were extracted from livers of NC and HFD mice (A), AAV-Vec and AAV-H19 mice (D), and WT and KO mice (G) fed ad libitum. Hnf4a promoter methylation was assessed by QMSP. (B, E, H) Relative Hnf4a mRNA levels as assessed by qPCR. (C, F, I) Relative protein levels as assessed by Western blotting. (J) Effects of H19 overexpression on hepatic insulin signaling. Proteins were extracted from livers of AAV-Vec– or AAV-H19–infected mice fed ad libitum and subjected to Western blot analysis. Quantifications (top panels) of INSR protein levels and AKT phosphorylation at Ser473 of the Western blots (bottom panel) are shown. n = 4–5 animals per group. Numbers are the mean ± SEM. *P < 0.05, **P < 0.01 based on Student t test. (K) A proposed model.