Esculin improve lipid accumulation in hepatocytes by inhibiting the PERK/eIF2A/ATF4 signaling pathway

Corresponding author: YE Xiaoting, yxt129@163.com

DOI: 10.12201/bmr.202409.00013

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  Abstract: Objective To explore the effect and mechanism of esculin on hepatocyte steatosis by inhibiting PERK/eIF2A/ATF4 signaling pathway. Methods Human normal liver cell line HL-7702 was used to induce a steatosis model of hepatocytes in vitro with 0.5 mmol/L free fatty acid (FFA, oleic acid: palmitic acid =2:1) and treated with 50, 200 μmol/L esculin for 24 h. After the cell samples were broken by ultrasound, the supernatant was collected and the contents of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), reduced glutathione and triglyceride were detected. Intracellular lipid droplets and the transcriptional levels of genes related to intracellular lipid metabolism were detected by Nile red fat fluorescence staining and qRT-PCR, respectively. Western blot was employed to detect the protein expressions of pro-apoptotic factors Caspase-3 and Bax, as well as the protein and phosphorylation levels related to PERK/eIF2A/ATF4 signaling pathway. Results The results confirmed that treatments of 50 and 200 μmol/L of esculin significantly decreased the levels of FFA-induced MDA, ALT and AST in hepatocytes (P < 0.05), and significantly increased the levels of intracellular GSH (P < 0.05). WB results showed that esculin treatment could significantly reduce the protein expression levels of Caspase-3 and Bax (P < 0.01). The results of Nile red staining and TG content detection confirmed that esculin treatment could significantly reduce the accumulation of intracellular lipid droplets and TG content (P < 0.05). The results of qRT-PCR showed that the expression levels of PPARγ, FASN, Srebf1, Dgat2, Mvk and Acaca in hepatocytes were significantly decreased after esculin treatment (P < 0.05). In terms of mechanism, the phosphorylation levels of PERK, eIF2A and ATF4 in hepatocytes were significantly reduced by esculin treatment (P < 0.05). Conclusion Esculin could improve lipid accumulation in hepatocytes by regulating the PERK/eIF2A/ATF4 signalling pathway, which plays a positive role in maintaining the healthy state of hepatocytes.

  Key words: hepatocyte; hepatocyte steatosis; lipid metabolism; PERK/eIF2A/ATF4

  Submit time: 10 September 2024

  Copyright: The copyright holder for this preprint is the author/funder, who has granted biomedRxiv a license to display the preprint in perpetuity.
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