The Protein Phosphatase PHLPP1 Suppresses Insulin Signaling and Inflammation in Mouse Model

Abstract

The PH domain Leucine Rich Repeat Protein Phosphatase 1 (PHLPP1) directly dephosphorylates and inactivates Akt2, the Akt isozyme that is a key transducer of insulin signaling. Elevated levels of PHLPP1 protein have been associated with obesity and insulin resistance in humans, suggesting PHLPP1 may be a novel therapeutic target to combat insulin resistance in diabetes and metabolic syndrome. Here we examine how loss of PHLPP1 affects insulin signaling using the Phlpp1−/− mice. Insulin tolerance tests of mice on a normal chow diet reveal a modest but statistically‐significant increase in the insulin sensitivity of mice lacking PHLPP1 compared to littermate Phlpp1+/+ controls. Analyses of liver from these mice reveal elevated Akt signaling in the mice lacking PHLPP1, as assessed by increased phosphorylation of Akt itself and downstream substrates such as GSK‐3 and MDM2. In addition, consistent with previous studies, the steady state levels of EGF receptor are elevated. We also note that there was an approximately 15% increase in the steady state levels of PHLPP2. Consistent with in vivo results, deletion of PHLPP1 in HepG2 liver cells also increases insulin‐dependent signaling, assessed by increased phosphorylation of the insulin receptor and Akt. Thus, both in vivo and in vitro studies are consistent with PHLPP1 suppressing insulin signaling. In contrast to results from normal chow diet, Phlpp1−/− and Phlpp1+/+ mice subjected to a high fat diet had the same insulin sensitivity. Furthermore, biochemical analysis of liver from these mice revealed a striking decrease in phosphorylation of Akt and downstream substrates such as S6kinase, and a decrease in PKCα. PHLPP2 levels remained elevated. Additionally, we also found that in livers, high fat diet promotes an up‐regulation of pro‐inflammatory genes such as Il6 and Tnfa, which is significantly enhanced in PHLPP1 deficient mice. Our data are consistent with a model in which loss of PHLPP1 enhances both insulin sensitivity and inflammation. The pro‐inflammatory effects of high fat diet may be exacerbated in the Phlpp1−/− cells, masking an insulin sensitivity phenotype.Support or Funding InformationThis work was funded by NIH P01DK054441This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.