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.