ATL I, Acts as a SIRT6 Activator to Alleviate Hepatic Steatosis in Mice via Suppression of NLRP3 Inflammasome Formation

Abstract

Accumulating evidence has highlighted that sirtuin-6 (SIRT6) plays an important role in hepatic gluconeogenesis and lipogenesis. We aim to investigate the underlying mechanisms and pharmacological interventions of SIRT6 on hepatic steatosis treatment. Herein, our results showed that atractylenolide I (ATL I) activated the deacetylase activity of SIRT6 to promote peroxisome proliferator-activated receptor alpha (PPARα) transcription and translation, while suppressing nuclear factor NF-kappa-B (NFκB)-induced NACHT, LRR, and PYD domains containing protein 3 (NLRP3) inflammasome formation. Together, these decreased the infiltration of F4/80 and CD11B positive macrophages, accompanied by decreased mRNA expression and serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL6), and interleukin-1 beta (IL1β). Additionally, these changes decreased sterol regulatory element-binding protein-1c (SREBP-1c) expression, while restoring carnitine O-palmitoyltransferase 1a (Cpt1a) expression, to decrease the size of adipocytes and adipose deposition, which, in turn, reversed high-fat diet (HFD)-induced liver weight and body weight accumulation in C57 mice. SIRT6 knockout or hepatic SIRT6 knockout in C57 mice largely abolished the effect of ATL I on ameliorating hepatic steatosis. Taken together, our results suggest that ATL I acts as a promising compound that activates SIRT6/PPARα signaling and attenuates the NLRP3 inflammasome to ameliorate hepatic inflammation and steatosis.

Molecular targets associated with ulcerative colitis and the benefits of atractylenolides-based therapy

“…Simultaneously, AT-I weakens NF-kB-mediated NLRP3 inflammasome formation, macrophage infiltration, and the expression levels of inflammatory cytokines such as TNF-α, IL-6 and IL-1β, thus suppressing hepatic inflammation and steatosis. Additionally, knocking out SIRT6 genes from mouse livers reduced the inhibitory effect of AT-I on NLRP3 inflammasomes and inflammatory responses induced by high-fat diets ( Kong et al, 2022 ). Inflammasomes are believed to mediate host defense against microbial pathogens while maintaining intestinal homeostasis, excessive activation can lead to inflammatory diseases such as CRC ( Beaugerie and Itzkowitz, 2015 ).…”