DL-norvaline attenuated HFD-induced metabolic inflammation and dysfunction with integrated pharmacokinetic,...

Metabolic inflammation is a major contributor to obesity-related metabolic disturbances, yet safe and bioavailable dietary candidates with multi-organ activity remain limited. DL-norvaline, a nonproteinogenic amino acid, was examined for its safety, pharmacokinetic characteristics, tissue distribution, and anti-inflammatory effects in models of high-fat diet (HFD)-induced obesity. Acute and subchronic oral toxicity studies showed no mortality or observable adverse effects, indicating a favorable safety margin. Pharmacokinetic analysis revealed rapid absorption, broad tissue distribution-particularly in liver, intestine, adipose tissue, and kidney-and approximately 20% cumulative excretion, suggesting systemic exposure without excessive accumulation. In vitro experiments using RAW264.7 macrophages demonstrated that DL-norvaline reduced LPS-induced expression of pro-inflammatory cytokines. In HFD-fed mice, DL-norvaline lowered LPS and inflammatory mediators, attenuated hepatic activation of multiple toll-like receptors and downstream MyD88/NF-κB signaling, and restored Nrf2-associated antioxidant genes. Improvements in oxidative stress, lipid-related gene expression, and liver injury further supported a protective role. Similar anti-inflammatory effects were observed in acute LPS-challenged and combined HFD-LPS models. Together, these findings indicate that DL-norvaline is a safe and systemically bioavailable amino acid that alleviates HFD-induced metabolic inflammation and dysfunction. The integrated toxicological, pharmacokinetic, and mechanistic results support its potential as a candidate for further development in the context of obesity-associated inflammatory disorders.