Long Noncoding RNA IncSHGL Recruits hnRNPAl to Suppress Hepatic Gluconeogenesis and Lipogenesis

摘要

Mammalian genomes encode a huge number of long noncoding RNAs (IncRNAs) with unknown functions. This study determined the role and mechanism of a new IncRNA, IncRNA suppressor of hepatic gluconeogenesis and lipogenesis (IncSHGL), in regulating hepatic glucose/ lipid metabolism. In the livers of obese mice and patients with nonalcoholic fatty liver disease, the expression levels of mouse IncSHGL and its human homologous IncRNA B4GALT1-AS1 were reduced. Hepatic IncSHGL restoration improved hyperglycemia, insulin resistance, and steatosis in obese diabetic mice, whereas hepatic IncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice. IncSHGL overexpression increased Akt phosphorylation and repressed gluconeogenic and lipogenic gene expression in obese mouse livers, whereas IncSHGL inhibition exerted the opposite effects in normal mouse livers. Mechanistically, IncSHGL recruited heterogeneous nuclear ribonucleoprotein A1 (hnRNPAl) to enhance the translation efficiency of CALM mRNAs to increase calmodulin (CaM) protein level without affecting their transcription, leading to the activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway and repression of the mTOR/SREBP-1C pathway independent of insulin and calcium in hepatocytes. Hepatic hnRNPAl overexpression also activated the CaM/Akt pathway and repressed the mTOR/SREBP-1C pathway to ameliorate hyperglycemia and steatosis in obese mice. In conclusion, IncSHGL is a novel insulin-independent suppressor of hepatic gluconeogenesis and lipogenesis. Activating the IncSHGL/hnRNPAl axis represents a potential strategy for the treatment of type 2 diabetes and steatosis.