β-Aminoisobutyric acid targets AMPK to suppress macrophage pro-inflammatory phenotype and alleviate lipopolysaccharide-induced sepsis in mice.

Abstract

Sepsis is a life-threatening syndrome caused by acute infection, marked by severe systemic inflammation and multi-organ dysfunction. Its pathogenesis involves excessive pro-inflammatory activation of macrophages. β-aminoisobutyric acid (BAIBA), a myokine produced during valine metabolism, has demonstrated beneficial effects on glucose and lipid metabolism, as well as anti-inflammatory and antioxidant properties. However, its potential to ameliorate lipopolysaccharide (LPS)-induced sepsis remains unknown. In this study, BAIBA pretreatment (150 and 500 mg/kg, orally) dose-dependently reduced mortality, systemic inflammation, and damage to the liver, lung, and kidney in LPS-induced septic mice. Notably, co-administration of BAIBA with low-dose dexamethasone (2 mg/kg, intravenous) provided enhanced therapeutic benefits. In septic mouse livers, BAIBA downregulated numerous inflammatory genes, reduced macrophage infiltration, and decreased the proportion of pro-inflammatory phenotypes. In vitro, BAIBA (10 and 20 μM) suppressed pro-inflammatory mediators and related genes in LPS/interferon-γ-stimulated RAW264.7 macrophages, accompanied by activation of the 5' AMP-activated protein kinase (AMPK) pathway. Similar anti-inflammatory effects were observed in bone marrow-derived macrophages and were abolished upon AMPK inhibition. Collectively, these findings underscore the protective role of BAIBA in sepsis- related dysfunction and macrophage activation.