| First Author | Meng X | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 20 | Pages | 10625-34 |
| PubMed ID | 27013659 | Mgi Jnum | J:234194 |
| Mgi Id | MGI:5789476 | Doi | 10.1074/jbc.M116.713768 |
| Citation | Meng X, et al. (2016) Liver MicroRNA-291b-3p Promotes Hepatic Lipogenesis through Negative Regulation of Adenosine 5'-Monophosphate (AMP)-activated Protein Kinase alpha1. J Biol Chem 291(20):10625-34 |
| abstractText | In a microarray study, we found that hepatic miR-291b-3p was significantly increased in leptin-receptor-deficient type 2 mice (db/db), a mouse model of diabetes. The function of miR-291b-3p is unknown. The potential role of miR-291b-3p in regulating hepatic lipid metabolism was explored in this study. High-fat diet (HFD)- and chow-fed mice were injected with an adenovirus expressing a miR-291b-3p inhibitor and a miR-291b-3p mimic through the tail vein. Hepatic lipids and lipogenic gene expression were analyzed. Additionally, gain- and loss-of-function studies were performed in vitro to identify direct targets of miR-291b-3p. MiR-291b-3p expression and the protein levels of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) were increased in the steatotic liver of db/db mice and HFD-fed mice versus their respective controls. Inhibition of hepatic miR-291b-3p expression prevented increases in hepatic lipogenesis and steatosis in HFD-fed mice. The opposite was observed when miR-291b-3p was overexpressed in the livers of chow-fed C57BL/6J wild-type mice. In vitro studies revealed that silencing of miR-291b-3p in NCTC1469 hepatic cells ameliorated oleic acid/palmitic acid mixture-induced elevation of cellular triglycerides. Importantly, we identified AMP-activated protein kinase (AMPK)-alpha1 as a direct target of miR-291b-3p. Using metformin, an activator of AMPK, we showed that AMPK activation-induced inhibition of hepatic lipid accumulation was accompanied by reduced expression of miR-291b-3p in the liver. Liver miR-291b-3p promoted hepatic lipogenesis and lipid accumulation in mice. AMPKalpha1 is a direct target of miR-291b-3p. In conclusion, our findings indicate that miR-291b-3p promotes hepatic lipogenesis by suppressing AMPKalpha1 expression and activity, indicating the therapeutic potential of miR-291b-3p inhibitors in fatty liver disease. |
