Integrated transcriptome and phosphoproteome analyses reveal that fads2 is critical for maintaining body LC-PUFA homeostasis

Fatty acid desaturate 2 (Fads2) is associated with many chronic diseases. Nevertheless, comprehensive researches on its role have not been performed. We here conducted an integrated analysis of long-chain polyunsaturated fatty acid (LC-PUFA) metabolism of fads2-deletion zebrafish (fads2^-/-) by transcriptomics, proteomics and phosphoproteomics. Compared with wild type zebrafish (WT), fads2^-/- showed significantly higher contents of hepatic linoleic acid (all-cis-9,12-C18:2), α-linolenic acid (all-cis-9,12,15-C18:3) and docosapetaenoic acid (all-cis-7,10,13,16,19-C22:5), and lower contents of γ-linolenic acid (all-cis-6,9,12-C18:3), stearidonic acid (all-cis-6,9,12,15-C18:4) and docosahexaenoic acid (all-cis-4,7,10,13,16,19-C22:6), accompanied by an increased n-6/n-3 PUFA level. In total, we identified 1608 differentially expressed genes (DEGs), 209 differentially expressed proteins (DEPs) and 153 differentially expressed phosphorylated proteins (DEPPs) with 190 sites between fads2^-/- and WT. Transcriptome and proteome analysis simultaneously aggregated these DEGs and DEPs into LC-PUFA synthesis and PPAR signaling pathways. Further interaction network analysis of the DEPPs showed that spliceosome and protein processing in endoplasmic reticulum pathway were critical groups. Additionally, we determined seven highly phosphorylated kinases and a highly expressed phosphatase in fads2^-/- zebrafish. These results give insights into the mechanism by which fads2 affects metabolic disease occurrence, and provide datasets for target selections for human disease treatment. SIGNIFICANCE: Balanced LC-PUFA composition was deeply associated with body health, while changes of LC-PUFAs usually induced serious diseases such as cardiovascular disease, type 2 diabetes and inflammatory disease. Fatty acid desaturase 2 (Fads2), subordinating to the fatty acid desaturase protein family, catalyzes the first desaturation reaction in LC-PUFA synthesis. Although Fads2 is associated with many chronic diseases including metabolic abnormalities, type 2 diabetes and obesity, comprehensive researches on its role have not been performed. On the basis of the integrated transcriptome, proteome and phosphoproteome analysis, we identified that fads2 was critical for maintaining body LC-PUFA homeostasis. Moreover, the crucial pathways including PPAR signaling pathway, spliceosome and protein processing in endoplasmic reticulum pathway, and candidate kinase targets associated with LC-PUFA metabolism were determined. These findings will contribute to the revealing of the mechanism and supply possible datasets for target selection for human disease treatment.