Introduction

Nonalcoholic fatty liver disease (NAFLD) is a continuous disease with an estimated global prevalence of 24 %, encompassing a wide histological spectrum rang from steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and even hepatocellular carcinoma (Lau, Zhang & Yu, 2017; Younossi et al., 2018). The occurrence of NASH was always characterized by lipid accumulation and inflammation (Schuster et al., 2018; Tomita et al., 2016). Certain evidence indicated AMPK (AMP-activated protein kinase) was a central energy mediator in NASH, which decreased NF-κB pathway and activated mitochondrial biogenesis (Herzig & Shaw, 2018; Liu et al., 2011; Strzyz, 2020; Wang et al., 2017). Differed from the above findings, STAT1 (signal transducers and activators of transcription) and CXCL10 (macrophage chemotactic ligand 10) could be regarded as potential targets for suppressing NASH in our present study. STAT1 induced the release of cytokines to initiate inflammatory response (Chmielewski et al., 2014). Blockade of STAT1 elevated the indicators of fatty acid oxidation in STAT1-/- mice (Sisler et al., 2015). Moreover, the decrease of STAT1 inhibited inflammatory response and prevented NASH and fibrosis (Grohmann et al., 2018). Generally, transcription factor STAT1 bound to CXCL10 promoter after its phosphorylated activation and nuclear translocation, and STAT1 inhibition reduced the release of CXCL10 (Tomita et al., 2017). CXCL10 contributed to inflammatory response in NASH model and emerged as a biomarker for the clinical diagnosis of NASH (Ibrahim et al., 2016; Zhang et al., 2014). No doubt, STAT1 and CXCL10 were closely related to lipid accumulation and inflammatory response. So the interference on the regulation of STAT1 and CXCL10 was a possible effective strategy for NASH treatment.
Diosmetin (3’, 5, 7-trihydroxy-4’-methoxy flavone, Dios), as a natural flavonoid (Liao et al., 2014), has a favorable effect against NASH through different mechanisms (Marcolin et al., 2012; Wu et al., 2019; Zheng et al., 2018). Recent studies demonstrated that Dios attenuated lipopolysaccharide / D-galactosamine (LPS/D-GalN)-induced acute hepatic failure correlating with MAPK pathway (Yang et al., 2017), and inhibited the activation of NLRP3 inflammasome in lung injury (Liu et al., 2018). Except that, Dios activated AMPK to alleviate the liver pathological changes and release of inflammatory factors in HFD-fed NAFLD rats (Zheng, Guo, Zhong & Jiang, 2018). What’s more, our previous study revealed that Dios exhibited an effect on lipid metabolism by promoting fatty acid oxidation in diabetes-mice. From these results, we reasonably assumed that Dios exerted a hepatoprotective effect against NASH. However, whether STAT1 and CXCL10 mediate the inhibition of Dios on NASH, and how to take advantage of the relations between the downstream proteins of STAT1 and CXCL10 to fully elucidate the underlying mechanism, and if this mechanism is beneficial for us to provide a new strategy for NASH treatment, all of these need to be investigated. In this study, we utilized the established models that HepG2 cells and C57BL/6J mice respectively induced by palmitic acid (PA) and high-fat diet (HFD) to identify the protective effect and potential mechanism of Dios against NASH through mediation of lipogenesis and alleviation of inflammatory response.