Abstract
Background/Objectives: Type 2 diabetes mellitus (T2DM) is a major metabolic disorder and is frequently accompanied by liver steatosis. Apolipoprotein J (ApoJ) is a glucose-regulated molecular chaperone that has been implicated in hepatic lipid deposition under nutrient overload. This study aimed to investigate the role of hepatocyte-specific ApoJ deletion in hepatic metabolism under diabetic conditions. Methods: A T2DM mouse model with hepatocyte-specific ApoJ knockout (HKO) was established through a high-fat diet combined with streptozotocin injection. Hepatic metabolic profiles were analyzed using untargeted metabolomics with UHPLC-MS/MS. Differential metabolites were subjected to KEGG pathway and Sankey diagram analyses to identify biologically relevant pathways. Results: In total, 140 metabolites showed significant differential abundance in HKO mouse liver, primarily encompassing organic acids and derivatives as well as lipids and lipid-like molecules. KEGG analysis revealed that ApoJ deletion enhanced pathways related to vitamin digestion and absorption, thiamine metabolism, amino acid biosynthesis, lysine degradation, and 2-oxocarboxylic acid metabolism. In contrast, pathways associated with galactose metabolism, cysteine and methionine metabolism, purine metabolism, and the pentose phosphate pathway were suppressed. Sankey diagram analysis further demonstrated that ApoJ deletion markedly reshapes hepatic metabolic networks in T2DM. Conclusions: Given the central role of hepatic dysmetabolism in the pathogenesis of diabetes and its complications, targeting ApoJ may represent a promising therapeutic approach for restoring hepatic metabolic homeostasis and preventing diabetes-associated steatosis.