Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia
Year: 2018
Type: article
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.
Source: JCI Insight
Institutions: Yale University, UConn Health, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Shanghai Medical College of Fudan University, Fudan University, Shanghai Jiao Tong University, Shanghai First People's Hospital, The First Affiliated Hospital, Sun Yat-sen University, Anhui Agricultural University, Inserm, Institut Cochin
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: American Diabetes Association, Yale University, China Scholarship Council, National Institutes of Health, Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, Yale University, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W2803378467