3 years ago

Long Non-coding RNA LncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis.

Yuhong Meng, Jichun Yang, Lin Dou, Jian Li, Biaoqi Feng, Qinghua Cui, Zhenzhen Chen, Weili Yang, Junpei Wang, Libo Sun, Ji Chen
Mammalian genomes encode a huge number of LncRNAs with unknown functions. This study determined the role and mechanism of a new LncRNA, LncRNA Suppressor of Hepatic Gluconeogenesis and Lipogenesis (LncSHGL), in regulating hepatic glucose/lipid metabolism. In the livers of obese mice and NAFLD patient, the expression levels of mouse LncSHGL and its human homologous LncRNA B4GALT1-AS1 were reduced. Hepatic LncSHGL restoration improved hyperglycemia, insulin resistance and steatosis in obese diabetic mice, whereas hepatic LncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice. LncSHGL overexpression increased Akt phosphorylation, and repressed gluconeogenic and lipogenic gene expression in obese mouse livers, whereas LncSHGL inhibition exerted the opposite effects in normal mouse livers. Mechanistically, LncSHGL recruited hnRNPA1 to enhance the translation efficiency of CALM mRNAs to increase CaM protein level without affecting their transcription, leading to the activation of PI3K/Akt pathway and repression of mTOR/SREBP-1C pathway independent of insulin and calcium in hepatocytes. Hepatic hnRNPA1 overexpression also activated CaM/Akt pathway and repressed mTOR/SREBP-1C pathway to ameliorate hyperglycemia and steatosis in obese mice. In conclusion, LncSHGL is a novel insulin-independent suppressor of hepatic gluconeogenesis and lipogenesis. Activating LncSHGL/hnRNPA1 axis represents a potential strategy for the treatment of type 2 diabetes and steatosis.

Publisher URL: http://doi.org/10.2337/db17-0799

DOI: 10.2337/db17-0799

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