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Quantitative proteomic profiling reveals hepatic lipogenesis and liver X receptor activation in the PANDER transgenic
Mark G Athanason1, Whitney A Ratliff1, Dale Chaput1
1Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, BSF 206, Tampa, FL 33620, USA.
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.
Insights
Pancreatic-derived factor (PANDER) impacts liver lipid metabolism and may cause selective hepatic insulin resistance (SHIR) by activating the liver X receptor (LXR) pathway, a finding relevant to type 2 diabetes.
Area of Science:
- Endocrinology
- Metabolomics
- Molecular Biology
Background:
- Pancreatic-derived factor (PANDER) is a novel hormone that regulates glycemic levels.
- Its precise mechanism in hepatic signaling is complex and not fully understood.
- PANDER's pleiotropic nature contributes to its intricate role in metabolic regulation.
Purpose of the Study:
- To elucidate the PANDER-induced hepatic signaling mechanism.
- To investigate the molecular basis of selective hepatic insulin resistance (SHIR) in PANDER transgenic (PANTG) mice.
- To explore the impact of PANDER on hepatic lipid metabolism.
Main Methods:
- Quantitative mass spectrometry-based proteomic analysis using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) to compare hepatic proteomes.
- Analysis of protein expression differences in PANTG mice under fasting, fed, and insulin-stimulated states.
- Western blot analysis and luciferase reporter assays to validate pathway activation.
Main Results:
- Proteomic analysis revealed significant alterations in lipid metabolism pathways across all metabolic states in PANTG mice.
- Key lipid metabolism proteins (ACC, ACLY, CD36, CYP7A1, FASN, SCD1) were differentially expressed.
- The liver X receptor (LXR) pathway was predicted to be activated, with increased LXRα and LXR-directed targets (FASN, CYP7A1) confirmed by Western analysis.
- Recombinant PANDER induced LXR promoter activity in vitro.
Conclusions:
- PANDER significantly influences hepatic lipid metabolism in a PANTG mouse model.
- The liver X receptor (LXR) pathway is a key mediator of PANDER's effects on hepatic lipid metabolism.
- PANDER may induce a SHIR phenotype, a condition relevant to type 2 diabetes, through LXR pathway activation.
