Abstract: Objective: To examine the impact of impaired branched-chain amino acid (BCAA) metabolism on hepatic β-amyloid (Aβ) deposition under conditions of insulin resistance. Methods: Thirty-two specific pathogen-free (SPF) male 3-month-old APP/PS1 mice were randomly allocated into four groups: control, high-fat diet (HFD), HFD with BCAA restriction, and HFD supplemented with BCAA groups. After 24 weeks of intervention, glucose tolerance was assessed. At study termination, all animals were fasted and euthanized; serum and liver tissue were collected. Serum BCAAs and their metabolites, branched-chain α-keto acids (BCKAs), were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Hepatic expression of key BCAA-catabolizing enzymes was determined by western blot. Serum insulin was measured by enzyme linked immunosorbent assay (ELISA); serum glucose, hepatic total cholesterol (TC), and triglycerides (TG) were assayed colorimetrically. Liver histopathology was observed by hematoxylin-eosin staining (HE), lipid deposition by Oil Red O staining, and Aβ accumulation in the liver by immunofluorescence. Results: After 24 weeks, compared with controls, the HFD group exhibited markedly elevated fasting serum glucose and insulin, impaired glucose tolerance, significantly increased hepatic TC and TG along with lipid droplets, significantly higher serum concentrations of three BCAAs and their corresponding metabolites BCKAs, and significantly increased phosphorylation level of branched-chain α-keto acid dehydrogenase (BCKDH) and protein expression level of branched-chain α-keto acid dehydrogenase kinase (BCKDK). Hepatic Aβ deposition was also increased. Relative to HFD, BCAA supplementation further raised serum concentrations of these BCAAs and BCKAs, whereas BCAA restriction significantly reduced all of them. Neither BCAA supplementation nor restriction significantly altered insulin sensitivity-related indicators such as fasting serum glucose, serum insulin, and glucose tolerance, nor did they alter hepatic TC, TG, or lipid droplet deposition. Nevertheless, BCAA supplementation aggravated hepatic Aβ deposition, whereas BCAA restriction alleviated it. Conclusion: Within the scope of this study, disturbed BCAA metabolism can modulate hepatic Aβ burden without markedly affecting systemic insulin sensitivity or intrahepatic lipid accumulation.

Key words: insulin resistance; branched-chain amino acids metabolic disorder; liver; β-amyloid deposition; high-fat diet