| First Author | Jing Y | Year | 2015 |
| Journal | J Hepatol | Volume | 62 |
| Issue | 6 | Pages | 1319-27 |
| PubMed ID | 25595884 | Mgi Jnum | J:273487 |
| Mgi Id | MGI:6293971 | Doi | 10.1016/j.jhep.2014.12.032 |
| Citation | Jing Y, et al. (2015) Hepatic p38alpha regulates gluconeogenesis by suppressing AMPK. J Hepatol 62(6):1319-27 |
| abstractText | BACKGROUND & AIMS: It is proposed that p38 is involved in gluconeogenesis, however, the genetic evidence is lacking and precise mechanisms remain poorly understood. We sought to delineate the role of hepatic p38alpha in gluconeogenesis during fasting by applying a loss-of-function genetic approach. METHODS: We examined fasting glucose levels, performed pyruvate tolerance test, imaged G6Pase promoter activity, as well as determined the expression of gluconeogenic genes in mice with a targeted deletion of p38alpha in liver. Results were confirmed both in vivo and in vitro by using an adenoviral dominant-negative form of p38alpha (p38alpha-AF) and the constitutively active mitogen-activated protein kinase 6, respectively. Adenoviral dominant-negative form of AMP-activated protein kinase alpha (DN-AMPKalpha) was employed to test our proposed model. RESULTS: Mice lacking hepatic p38alpha exhibited reduced fasting glucose level and impaired gluconeogenesis. Interestingly, hepatic deficiency of p38alpha did not result in an alteration in CREB phosphorylation, but led to an increase in AMPKalpha phosphorylation. Adenoviral DN-AMPKalpha could abolish the effect of p38alpha-AF on gluconeogenesis. Knockdown of up-steam transforming growth factor beta-activated kinase 1 decreased the AMPKalpha phosphorylation induced by p38alpha-AF, suggesting a negative feedback loop. Consistently, inverse correlations between p38 and AMPKalpha phosphorylation were observed during fasting and in diabetic mouse models. Importantly, adenoviral p38alpha-AF treatment ameliorated hyperglycemia in diabetic mice. CONCLUSIONS: Our study provides evidence that hepatic p38alpha functions as a negative regulator of AMPK signaling in maintaining gluconeogenesis, dysregulation of this regulatory network contributes to unrestrained gluconeogenesis in diabetes, and hepatic p38alpha could be a drug target for hyperglycemia. |
