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cAMP response element-binding protein (CREB) regulated transcriptional coactivator 2 (CRTC2) is a critical transcription factor that maintains glucose homeostasis by activating CREB. Energy homeostasis is maintained through multiple pathways; therefore, CRTC2 may interact with other transcription factors, particularly under metabolic stress. CRTC2 liver-specific knockout mice were created, and the global proteome, phosphoproteome, and acetylome from liver tissue under high-fat diet conditions were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. Differentially regulated proteins (DRPs) were enriched in metabolic pathways, which was subsequently corroborated through animal experiments. The consensus DRPs from these datasets were used as seed proteins to generate a protein-protein interaction (PPI) network using STRING, and GeneMANIA identified fatty acid synthase (FASN) as a mutually relevant protein. In an additional local-PPI (LPPI) analysis of CRTC2 and FASN with DRPs, sterol regulatory element binding transcription factor 1 (SREBF1) was the common mediator. CRTC2-CREB and SREBF1 are transcription factors and DNA-binding motif analysis showed that multiple CRTC2-CREB regulated genes possess SREBF1 binding motifs. This indicates the possible induction by the CRTC2-SREBF1 complex, which is validated through luciferase assay. Therefore, the CRTC2-SREBF1 complex potentially modulates the transcription of multiple proteins that fine-tune cellular metabolism under metabolic stress. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
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