Silybin inhibits NLRP3 inflammasome assembly through the NAD⁺/SIRT2 pathway in mice with nonalcoholic fatty liver disease

Abstract

Silybin is one of the effective, traditional Chinese medicines used as a hepatoprotective agent in nonalcoholic fatty liver disease (NAFLD) therapy worldwide, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been recognized as an important factor involved in NAFLD development. However, little is known about the mechanisms of silybin in the regulation of high-fat diet (HFD)-induced liver inflammation. In our study, we found that silybin inhibited endoplasmic reticulum stress and NLRP3 inflammasome activation in the livers of HFD-fed mice and in cultured hepatocytes. Phosphorylation of inositol-requiring enzyme (IRE)1α and eIF2α, expression of thioredoxin-interacting protein and cleaved caspase-1, and release of IL-1β were reduced by silybin. In addition, silybin inhibited the approach of calreticulin and translocase of outer membrane 20 (Tom20), prevented assembly of the NLRP3 inflammasome complex, and suppressed the accumulation of acetylated α-tubulin in the perinuclear region. Both MEC-17 and sirtuin 2 (SIRT2) were influenced by palmitate and silybin, whereas histone deacetylase 6 was not affected. In addition, supplementing NAD directly or increasing NAD concentration with silybin could maintain the activity of SIRT2. The anti-inflammatory effect of silybin was blocked by SIRT2 silencing or by the SIRT2 inhibitor AGK2, as evidenced by NLRP3/ASC colocalization, AC-α-tubulin expression, and IL-1β release. These findings indicate that the NAD/SIRT2 pathway is an important mediator through which silybin prevents NLRP3 inflammasome activation during NAFLD.-Zhang, B., Xu, D., She, L., Wang, Z., Yang, N., Sun, R., Zhang, Y., Yan, C., Wei, Q., Aa, J., Liu, B., Wang, G., Xie, Y. Silybin inhibits NLRP3 inflammasome assembly through the NAD/SIRT2 pathway in mice with nonalcoholic fatty liver disease.

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

“…Therefore, SIRT2 acts as a negative regulator of NLRP3 inflammasome activity [27]. Consistent with this study, other groups also reported that blockade of acetylation or restoration of intracellular NAD + levels with various pharmaceuticals abrogates this phenomenon [127,128]. SIRT2 also removes acetyl groups from NLRP3 to block the complex assembly [129].…”

hADSCs derived extracellular vesicles inhibit NLRP3inflammasome activation and dry eye

“…Here we demonstrated that hADSC-Evs application block the upregulation of NLRP3 and increased maturation of IL-1β HCECs in response to hyperosmotic stress, which was confirmed by corneal and conjunctival samples of DED mice, indicating that hADSC-Evs alleviated DED progression via inhibiting NLRP-3-IL-1β signaling axis. Indeed, previous studies have reported that MSC-EVs therapy for acute liver failure (ALF) through reduction of NLRP3 inflammasome 35,36 . However, the precise mechanisms of how hADSC-Evs regulate NLRP3 activation were not detected in this study, which deserves future investigations.…”

Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases

“…Specifically, silymarin inhibits/suppresses: (a) the TNF‐α‐induced activation of mitogen‐activated protein kinase and c‐Jun N‐terminal kinase and as well as the TNF‐α‐induced cytotoxicity and caspase activation (Gharagozloo et al, ; Saller, Brignoli, Melzer, & Meier, ), (b) both the kappa B motif of NF‐κB DNA binding activity and its dependent gene expression in hepatoma cells as well as the translocation of NF‐κB p65 protein through phosphorylation to the nucleus without affecting its ability to bind the DNA, and (c) lipopolysaccharides (LPS)‐induced production of NO in isolated mouse peritoneal macrophages (Kim, Lee, & Jeon, ). Finally, a recent relevant study has shown that the NAD+/SIRT2 pathway is an important mediator through which silybin prevents the NLRP3 inflammasome activation in mice with liver steatosis (Zhang et al, ).…”