[Dietary serine supplementation inhibits the hepatic macrophage AKT/mTOR pathway and improves primary biliary...

Objective: To investigate the correlation between serum serine levels and the degree of severity of primary biliary cholangitis (PBC) so as to elucidate the protective effect and molecular mechanism of serine supplementation in cholestatic liver disease. Methods: Serum serine levels were measured in 62 cases with PBC patients diagnosed at Tianjin Medical University General Hospital from January 2021 to June 2023, and their correlation with serological indicators and liver pathological scores was analyzed. A C57BL/6J mouse model of cholestatic liver injury was established by inducing a 0.1% dimethylnitrosamine (DDC) diet. Serum biochemical indicators, hepatic inflammatory factor mRNA expression, liver histopathological changes, macrophage M1 polarization marker (CD86), and protein expression in the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway were intervened through dietary serine supplementation. In vitro experiments were conducted by stimulating RAW264.7 macrophages with lipopolysaccharide (LPS) to observe the effects of serine on inflammatory factors, M1 polarization, and the AKT/mTOR pathway. Intergroup comparisons for measurement data were performed using independent sample t-tests or Wilcoxon rank-sum tests. Correlations between serum serine levels and the above serological indicators and liver pathological scores were analyzed using Pearson or Spearman methods. Results: Serum serine levels were significantly negatively correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (γ-glutamyltransferase), total bilirubin, immunoglobulin G, and liver pathological scores in patients with PBC (P<0.05). Dietary serine supplementation significantly improved cholestasis in DDC mice, inhibited the expression of hepatic tumor necrosis factor-α, interleukin-1β, and interleukin-6 mRNA (P<0.05), reduced portal inflammatory infiltration, and decreased CD86⁺M1 macrophage infiltration and p-AKT/p-mTOR co-localization (P<0.05). In vitro experiments showed that serine intervention inhibited lipopolysaccharide-induced macrophage M1 polarization and inflammatory cytokine expression and downregulated p-AKT/p-mTOR protein expression (P<0.05). Conclusion: Reduced serum serine levels are associated with the degree of severity of PBC. Dietary serine supplementation can inhibit the hepatic macrophage AKT/mTOR signaling pathway and block M1 polarization and inflammatory responses, thereby improving cholestatic liver injury.