Hepatic lipidomics reveals lipid metabolism reprogramming response to different branched-chain amino acids interventions in nonalcoholic fatty liver disease of laying hens.

Dietary restrictions of protein or branched-chain amino acids (BCAA) reprogram lipid metabolism and ameliorate metabolic health. However, dietary high protein (enriched in BCAA) or BCAA supplementation is effective for the therapy of nonalcoholic fatty liver disease (NAFLD), yet their metabolic effects on hepatic lipidomic changes and how the response to different BCAA interventions have not been systemically characterized. Here, we comprehensively analyzed the hepatic lipid landscape following different BCAA interventions and identified over 1400 unique lipid species. Strikingly, we find that High Leu intervention upregulates the synthesis of diacylglycerols (DGs) and monoacylglycerols (MGs), and preferentially downregulates glycerophospholipid metabolism and autophagy, but fails to activate the mitogen-activated protein kinase (MAPK) pathway. High Ile and High LeuIle interventions activate glycerophospholipid metabolism and induce the inhibition of MAPK and autophagy signaling pathways, whereas they are toxic and adverse to metabolic health and contribute to insulin resistance. Intriguingly, we find High BCAA feeding strongly reprograms the hepatic lipidome by activating the MAPK and autophagy signaling pathways and downregulating glycerophospholipid metabolism. By integrating multiomics approaches, we uncovered the cross-talk between amino acid metabolism, tryptophan metabolites, and lipidome remodeling in response to High BCAA intervention. Our results highlight the differential hepatic lipidome alterations in response to distinct dietary BCAA interventions and suggest that modest BCAA supplementation may serve as a new approach for treating and preventing metabolic dysfunction-associated fatty liver disease (MASLD) in humans and fatty liver hemorrhagic syndrome (FLHS) in laying hens.