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

JCI Insight
Na ZhangYingqun Huang

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.

Associated Clinical Trials

References

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Citations

May 7, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tiefeng CaoYingqun Huang
Jun 18, 2020·International Journal of Molecular Sciences·Ariadna Pielok, Krzysztof Marycz
Aug 9, 2020·Frontiers in Endocrinology·Tie-Ning ZhangChun-Feng Liu
Jan 19, 2020·Nature Communications· Da LiYingqun Huang
Jul 24, 2020·Molecular Medicine·Xian ShiGuo-Jun Zhao
Dec 10, 2020·JHEP Reports : Innovation in Hepatology·Amin Mahpour, Alan C Mullen
Apr 17, 2020·Mechanisms of Ageing and Development·Xiaoying Jiang, Qilan Ning
Feb 6, 2020·Cell Reports·Yetao XuYingqun Huang
Nov 24, 2020·Translational Research : the Journal of Laboratory and Clinical Medicine·Zhihong YangSuthat Liangpunsakul
Mar 31, 2021·Molecular and Cellular Endocrinology·Jianguo WuLi Wang
Apr 4, 2021·Molecular and Cellular Endocrinology·Hai-Yan WuHe-Feng Huang
Apr 24, 2021·Genes & Development·Lara BideyanPeter Tontonoz
Jun 17, 2021·Expert Review of Molecular Diagnostics·Ana Iris Hernández-AguilarEugenia Flores-Alfaro
Jul 25, 2021·International Journal of Molecular Sciences·Vianet Argelia Tello-FloresEugenia Flores-Alfaro
May 27, 2020·Experimental and Molecular Pathology·Xiaojiaoyang Li, Runping Liu
Oct 28, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Qian ZhangXiaojing Wang

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Datasets Mentioned

BETA
GSE103437

Methods Mentioned

BETA
PCR
methylation profiling
ELISA
transfection
RNA-seq
electrophoresis
RIP
Assay

Software Mentioned

DESeq2
ZR
Illumina
Bismark
QMSP
GraphPad Prism
RNA
Seq Alignment

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