Age-Dependent Loss of Hepatic SIRT1 Enhances NLRP3 Inflammasome Signaling and Impairs Capacity for Liver Fibrosis Resolution
Abstract
Our studies indicate that the longevity factor SIRT1 is implicated in metabolic disease; however, whether and how hepatocyte-specific SIRT1 signaling is involved in liver fibrosis remains undefined. We characterized a functional link of age-mediated defects in SIRT1 to the NLRP3 inflammasome during age-related liver fibrosis. In multiple experimental murine models of liver fibrosis, we compared the development of liver fibrosis in young and old mice, as well as in liver-specific SIRT1 knockout (SIRT1 LKO) mice and wild-type (WT) mice. Liver injury, fibrosis, and inflammation were assessed histologically and quantified by real-time PCR analysis. In a model of hepatotoxininduced liver fibrosis, old mice displayed more severe and persistent liver fibrosis than young mice during liver injury and after injury cessation, as characterized by inhibition of SIRT1, induction of NLRP3, infiltration of macrophages and neutrophils, activation of hepatic stellate cells (HSCs), and excessive deposition and remodeling of the extracellular matrix. Mechanistically, deletion of SIRT1 in hepatocytes resulted in NLRP3 and IL-1β induction, pro-inflammatory response, and severe liver fibrosis in young mice, mimicking the ability of aging to impair the resolution of established fibrosis. In an aging mouse model, chronic-plus-binge alcohol feeding-induced liver fibrosis was attenuated by treatment with MCC950, a selective NLRP3 inhibitor. NLRP3 inhibition ameliorated alcoholic liver fibrosis in old mice by repressing inflammation and reducing hepatocyte-derived danger signaling—ASK1 and HMGB1. In conclusion, age-dependent SIRT1 defects lead to NLRP3 activation and inflammation, which in turn impairs the capacity to resolve fibrosis during aging.
Jennifer Adjei-Mosi1,2 | Qing Sun1,2 | Steven Blake Smithson1,2 | Gavyn Lee Shealy1,2 | Krupa Dhruvitha Amerineni1,2 | Zerong Liang1,2 | Hanqing Chen1,2 | Mei Wang1,2 | Qinggong Ping1,2 | Jingyan Han3 | Masahiro Morita1,2 | Amrita Kamat1,4 | Nicolas Musi1,4 | Mengwei Zang1,2,4