Reprogramming of hepatic BCAA metabolism by fructose exacerbates hepatic steatosis

Excessive fructose intake is a major dietary factor that promotes hepatic steatosis. Branched-chain amino acid (BCAA) catabolism has recently been implicated in hepatic lipid homeostasis, but whether fructose overload affects hepatocyte BCAA catabolism and whether this contributes to fructose-induced lipid dysregulation remain unclear. Here, we examined hepatic BCAA metabolic responses to fructose using acute fructose gavage, intraperitoneal fructose administration, primary hepatocyte stimulation, and hepatocyte-specific Bckdha-deficient mice. Acute fructose gavage rapidly altered hepatic BCAA catabolic markers, and this effect was recapitulated by intraperitoneal fructose administration, indicating that systemic fructose exposure is sufficient to perturb hepatic BCAA metabolism. Consistently, fructose suppressed BCAA catabolic gene expression in isolated primary hepatocytes. Functionally, hepatocyte-specific Bckdha deficiency aggravated fructose-induced hepatic lipid accumulation and enhanced the expression of genes involved in de novo lipogenesis, including Srebf1, Acaca, Fasn, Scd1, and Elovl6. Collectively, these findings suggest that fructose overload suppresses hepatocyte BCAA catabolism and that impaired BCAA catabolism amplifies fructose-induced hepatic lipogenic programs and lipid accumulation.