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Low birth weight (LBW) is associated with metabolic disorders in early life. While dietary l-tryptophan (Trp) can ameliorate postprandial plasma triglycerides (TG) disposal in LBW piglets, the genetic and biological basis underlying Trp-caused alterations in lipid metabolism is poorly understood. In this study, we collected 24 liver samples from 1-mo-old LBW and normal birth weight (NBW) piglets supplemented with different concentrations of dietary Trp (NBW with 0% Trp, N0; LBW with 0% Trp, L0; LBW with 0.4% Trp, L4; LBW with 0.8% Trp, L8; N = 6 in each group.) and conducted systematic, transcriptome-wide analysis using RNA sequencing (RNA-seq). We identified 39 differentially expressed genes (DEG) between N0 and L0, and genes within "increased dose effect" clusters based on dose-series expression profile analysis, enriched in fatty acid response of gene ontology (GO) biological process (BP). We then identified RNA-binding proteins including SRSF1, DAZAP1, PUM2, PCBP3, IGF2BP2, and IGF2BP3 significantly (P &lt; 0.05) enriched in alternative splicing events (ASE) in comparison with L0 as control. There were significant positive and negative relationships between candidate genes from co-expression networks (including PID1, ANKRD44, RUSC1, and CYP2J34) and postprandial plasma TG concentration. Further, we determined whether these candidate hub genes were also significantly associated with metabolic and cardiovascular traits in humans via human phenome-wide association study (Phe-WAS), and analysis of mammalian orthologs suggests a functional conservation between human and pig. Our work demonstrates that transcriptomic changes during dietary Trp supplementation in LBW piglets. We detected candidate genes and related BP that may play roles on lipid metabolism restoration. These findings will help to better understand the amino acid support in LBW metabolic complications.

RNA-seq reveals insights into molecular mechanisms of metabolic restoration via tryptophan supplementation in low birth weight piglet model