Abstract
PANcreatic-DERived factor (PANDER) is a member of a superfamily of FAM3 proteins modulating glycemic levels by metabolic regulation of the liver and pancreas. The precise PANDER-induced hepatic signaling mechanism is still being elucidated and has been very complex due to the pleiotropic nature of this novel hormone. Our PANDER transgenic (PANTG) mouse displays a selective hepatic insulin resistant (SHIR) phenotype whereby insulin signaling is blunted yet lipogenesis is increased, a phenomena observed in type 2 diabetes. To examine the complex PANDER-induced mechanism of SHIR, we utilized quantitative mass spectrometry-based proteomic analysis using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) to reveal the global hepatic proteome differences within the PANTG under the metabolic states of fasting, fed and insulin-stimulated conditions. Proteomic analysis identified lipid metabolism as one of the top cellular functions differentially altered in all metabolic states. Differentially expressed proteins within the PANTG having a lipid metabolic role included ACC, ACLY, CD36, CYP7A1, FASN and SCD1. Central to the differentially expressed proteins involved in lipid metabolism was the predicted activation of the liver X receptor (LXR) pathway. Western analysis validated the increased hepatic expression of LXRα along with LXR-directed targets such as FASN and CYP7A1 within the PANTG liver. Furthermore, recombinant PANDER was capable of inducing LXR promoter activity in-vitro as determined by luciferase reporter assays. Taken together, PANDER strongly impacts hepatic lipid metabolism across metabolic states and may induce a SHIR phenotype via the LXR pathway.