Hesperidin suppresses ERS-induced inflammation in the pathogenesis of non-alcoholic fatty liver disease.

Qi Xie,Zengning Li,Shuqing Gao,Min Lei

doi:10.18632/aging.203817

Abstract

Objective: The current study aimed to establish a non-alcoholic fatty liver disease (NAFLD) model using HFD-fed SD rats and FFA-stimulated human THP-1 cells to examine whether hesperidin (HSP) plays a role in endoplasmic reticulum stress (ERS)-induced inflammation in the pathogenesis of NAFLD.Methods: Oil red O staining was used to determine the effect of HSP on hepatic steatosis in rat liver tissues. Differentially expressed genes (DEGs) were subjected to functional enrichment analysis by bioinformatics. Western blotting was used to detect the protein expression of GRP94, ATF6, ATF4, p-PERK, p-IRE1α, IL-1β, IL-6, and TNF-α in liver tissues and THP-1 cell lines, and the expression of GRP94 and p-PERK in vitro was detected through immunofluorescence staining.Results: HSP significantly decreased the weight gain, hepatic steatosis but not serum lipid profile and suppressed the serum levels of inflammatory factors in HFD-fed rats. It was revealed by bioinformatics analysis that the inflammatory response and IRE1α activation were enriched signaling pathways in NAFLD. The expression of ERS-related biomarkers, GRP94, ATF6, ATF4, p-PERK and p- IRE1α, was significantly suppressed by HSP in vivo and in vitro. Moreover, the inflammatory markers, including IL-1β, IL-6, and TNF-α, were also decreased by HSP in vivo and in vitro. Immunofluorescence staining exposed that the expression of GRP94 and p-PERK was decreased by HSP in vitro.Conclusion: HSP may suppress ERS-induced inflammation in the pathogenesis of NAFLD.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic disease with a series of liver disorders, eventually resulting in cirrhosis and hepatocellular carcinoma [1, 2]
Rats were fed with normal diet (ND) and high-fat diet (HFD), and gavaged with the same volume of normal saline and HSP (200 mg/kg.bw) for 12 weeks to induce NAFLD
Oil red O positive areas/total areas for lipid deposition revealed that HFD markedly increased the lipid deposition in livers of rats compared with that in CD-fed rats, and such an increase was significantly diminished by HSP (P < 0.05, Figure 1D)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic disease with a series of liver disorders, eventually resulting in cirrhosis and hepatocellular carcinoma [1, 2]. Owing to the global obesity pandemic, the prevalence of NAFLD is continually growing worldwide, and a fast rise in NAFLD prevalence has been perceived in China [3, 4]. Due to the increasing growth in childhood obesity and more weakness to genomic and ecological reasons, NAFLD currently influences more and more pediatric populations [5, 6]. NAFLD is swiftly becoming a leading public health problem worldwide [7]. No applicable drug therapeutic strategy for NAFLD has been recognized.

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Results

Conclusion