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JCI Insight. 2018 May 17;3(10). pii: 120304. doi: 10.1172/jci.insight.120304. eCollection 2018 May 17.

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

Author information

1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, Connecticut, USA.
3
Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, China.
4
Department of Cardiology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
5
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
6
Department of Gynecology and Obstetrics, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
7
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
8
Department of Veterinary Medicine, College of Animal Science and Technology, Anhui Agricultural University, Hefei, Anhui, China.
9
Department of Genetics and Development, Inserm U1016, Institut Cochin, Paris, France.

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.

KEYWORDS:

Diabetes; Endocrinology; Glucose metabolism; Metabolism; Noncoding RNAs

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