Abstract
The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the regulation of HMGB1 in NAFLD, particularly through sirtuin 1 (SIRT1), remains unclear. In this study, we investigated the role of SIRT1-mediated inhibition of HMGB1 release in NAFLD and the effect of salvianolic acid B (SalB), which is a water-soluble phenolic acid extracted from Radix Salvia miltiorrhiza, on NAFLD through SIRT1/HMGB1 signaling. In vivo, SalB treatment significantly attenuated high-fat diet (HFD)-induced liver damage, hepatic steatosis, and inflammation. Importantly, SalB significantly inhibited HMGB1 nuclear translocation and release, accompanied by SIRT1 elevation. In HepG2 cells, palmitic acid (PA)-induced pro-inflammatory cytokines release were blocked by HMGB1 small interfering RNA (siRNA) transfection. Moreover, pharmacological SIRT1 inhibition by Ex527 induced HMGB1 translocation and release, whereas SIRT1 activation by resveratrol or SalB reversed this trend. SIRT1 siRNA abrogated the SalB-mediated inhibition of HMGB1 acetylation and release, suggesting that SalB-mediated protection occurs by SIRT1 targeting HMGB1 for deacetylation. We are the first to demonstrate that the SIRT1/HMGB1 pathway is a key therapeutic target for controlling NAFLD inflammation and that SalB confers protection against HFD- and PA-induced hepatic steatosis and inflammation through SIRT1-mediated HMGB1 deacetylation.
Highlights
Compared with the control group, the serum levels of total cholesterol (TC) and triglyceride (TG), which are sensitive serum biomarkers of liver steatosis, were remarkably increased in the high-fat diet (HFD) group, while Salvianolic acid B (SalB) treatment reversed this trend (Fig. 1B). Both H&E staining and Sudan IV staining of liver sections showed the accumulation of lipid droplets in the livers of the HFD-fed animals, whereas lipid droplets were rare in livers of the control animals and the rats that were treated with SalB alone (Fig. 1C,D)
The present study represents the first attempt to demonstrate that 1) the sirtuin 1 (SIRT1)/HMGB1 pathway is a pivotal therapeutic target for preventing Non-alcoholic fatty liver disease (NAFLD) progression, 2) SalB confers protection against HFD- and palmitic acid (PA)-induced hepatic steatosis and inflammation, and 3) the protective effect of SalB may be associated with the SIRT1/HMGB1 pathway
The HMGB1 proteins in (A) the whole-cell lysate and (B) the culture medium were measured by Western blotting. **P < 0 .01 vs. the si-Control group, ##P < 0 .01 vs. the PA group pretreated with control small interfering RNA (siRNA) (n = 3). (C) TNF-α and (D) IL-8 levels in the culture medium were measured by ELISA
Summary
Recent studies have demonstrated that HMGB1 is acetylated and released from hepatocytes in liver ischemia/reperfusion (I/R) and have identified decreased HDAC1 and HDAC4 as critical for regulating acetylated HMGB1 release from neurons in response to ethanol exposure[21,22]. It is unknown whether the acetylation of HMGB1 regulates its release from hepatocytes during the pathogenesis of NAFLD. The purposes of the present study were to investigate whether SIRT1-mediated HMGB1 deacetylation can modulate the release of HMGB1 during the progression of NAFLD and to explore whether SalB can protect against NAFLD via the SIRT1/HMGB1 pathway
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