SIRT1 inhibited LPS- or TNF-α-induced HMGB1 release from macrophages by directly interacting with HMGB1 in an acetylation-dependent manner; therefore, we next analyzed whether SIRT1 affected the circulating HMGB1 level during endotoxemia, a standard model of systemic inflammation. Here, HMGB1 is linked to serum lipopolysaccharide activity.