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. 2024 Jan 12;24(1):36.
doi: 10.1186/s12906-024-04336-1.

Hugan Qingzhi tablets attenuates endoplasmic reticulum stress in nonalcoholic fatty liver disease rats by regulating PERK and ATF6 pathways

Miaoting Yang  1 , Xiaorui Yao  2 , Fan Xia  3 , Shijian Xiang  3 , Waijiao Tang  4 , Benjie Zhou  5
Affiliations

Hugan Qingzhi tablets attenuates endoplasmic reticulum stress in nonalcoholic fatty liver disease rats by regulating PERK and ATF6 pathways

Miaoting Yang et al. BMC Complement Med Ther. .

Abstract

Background: Endoplasmic reticulum (ER) stress, promoting lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Hugan Qingzhi tablets (HQT) has a definite effect in the clinical treatment of NAFLD patients, but its mechanism is still unclear. This study aims to investigate the effects of HQT on ER stress in the liver tissues of NAFLD rats and explore the underlying mechanism.

Methods: The NAFLD rat model was managed with high-fat diet (HFD) for 12weeks. HQT was administrated in a daily basis to the HFD groups. Biochemical markers, pro-inflammatory cytokines, liver histology were assayed to evaluate HQT effects in HFD-induced NAFLD rats. Furthermore, the expression of ER stress-related signal molecules including glucose regulating protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), p-PERK, eukaryotic translation initiation factor 2α (EIF2α), p-EIF2α, activating transcription factor 4 (ATF4), acetyl-coenzyme A-carboxylase (ACC), activating transcription factor (ATF6), and nuclear factor-kappa B-p65 (NF-κB-p65) were detected by western blot and/or qRT-PCR.

Results: The histopathological characteristics and biochemical data indicated that HQT exhibited protective effects on HFD-induced NAFLD rats. Furthermore, it caused significant reduction in the expression of ERS markers, such as GRP78, PERK, p-PERK, and ATF6, and subsequently downregulated the expression of EIF2α, p-EIF2α ATF4, ACC, and NF-κB-p65.

Conclusions: The results suggested that HQT has protective effect against hepatic steatosis and inflammation in NAFLD rats by attenuating ER stress, and the potential mechanism is through inhibition of PERK and ATF6 pathways.

Keywords: Chinese traditional medicine; Endoplasmic reticulum stress (ERS) pathway; Hepatoprotective effect; Hugan Qingzhi tablets (HQT); Non-alcoholic fatty liver disease (NAFLD).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Hugan Qingzhi tablets attenuates endoplasmic reticulum stress in nonalcoholic fatty liver disease rats by regulating PERK and ATF6 pathways. ↑: up-regulation; ↓: down-regulation
Fig. 2
Fig. 2
Rat body weight (a) and hepatic index (b) changes. Con: control group; HFD: high-fat diet group; FF: HFD + fenofibrate group; HL: HFD + HQT low dosage group; HM: HFD + HQT moderate dosage group; HH: HFD + HQT high dosage group. * p < 0.05, ** p < 0.01 versus Con group. # p < 0.05, ## p < 0.01 versus HFD group
Fig. 3
Fig. 3
Effects of HQT on the serum levels of ALT, AST, TG, TC, LDL-C and HDL-C in NAFLD rats. Con: control group; HFD: high-fat diet group; FF: HFD + fenofibrate group; HL: HFD + HQT low dosage group; HM: HFD + HQT moderate dosage group; HH: HFD + HQT high dosage group. * p < 0.05, ** p < 0.01 versus Con group. # p < 0.05, ## p < 0.01 versus HFD group
Fig. 4
Fig. 4
Effects of HQT on the levels of TNF-α, IL-6 and IL-1β in NAFLD rat livers. Con: control group; HFD: high-fat diet group; FF: HFD + fenofibrate group; HL: HFD + HQT low dosage group; HM: HFD + HQT moderate dosage group; HH: HFD + HQT high dosage group. * p < 0.05, ** p < 0.01 versus Con group. # p < 0.05, ## p < 0.01 versus HFD group
Fig. 5
Fig. 5
Effects of HQT on histopathological examination by H&E and Oil Red O (400× magnification). Con: control group; HFD: high-fat diet group; FF: HFD + fenofibrate group; HL: HFD + HQT low dosage group; HM: HFD + HQT moderate dosage group; HH: HFD + HQT high dosage group
Fig. 6
Fig. 6
Transmission electron microscopy of the ER in each group of hepatocytes (5000× magnification, 10,000× magnification). Li: lipid, M: mitochondria, Er: endoplasmic reticulum. Con: control group; HFD: high-fat diet group; HH: HFD + HQT high dosage group
Fig. 7
Fig. 7
Effect of HQT on PERK pathway proteins and mRNA of ERS. a-f The expression levels of GRP78, PERK, p-PERK, EIF2α, p-EIF2α, ATF4 and ACC protein in rat liver tissues. g-i The expression levels of GRP78, ATF6 and ACC mRNA in rat liver tissues. Con: control group; HFD: high-fat diet group; FF: HFD + fenofibrate group; HL: HFD + HQT low dosage group; HM: HFD + HQT moderate dosage group; HH: HFD + HQT high dosage group. * p < 0.05, ** p < 0.01 versus Con group. # p < 0.05, ## p < 0.01 versus HFD group
Fig. 8
Fig. 8
Effect of HQT on ATF6 pathway proteins and mRNA of ERS. a-c The expression levels of ATF6 and NF-κB-p65 protein in rat liver tissues. d The expression levels of ATF6 mRNA in rat liver tissues. Con: control group; HFD: high-fat diet group; FF: HFD + fenofibrate group; HL: HFD + HQT low dosage group; HM: HFD + HQT moderate dosage group; HH: HFD + HQT high dosage group. * p < 0.05, ** p < 0.01 versus Con group. # p < 0.05, ## p < 0.01 versus HFD group
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