Omega‑3 polyunsaturated fatty acids inhibit IL‑11/STAT3 signaling in hepatocytes during acetaminophen hepatotoxicity.

Abstract

Omega‑3 polyunsaturated fatty acids (n‑3 PUFAs) exert a negative effect on IL‑6 production in several liver disorders, including cirrhosis, acute liver failure and fatty liver disease. However, its effect on the production of IL‑11, another important IL‑6 family cytokine, remains unclear. IL‑11 was found to be significantly elevated in acetaminophen (APAP)‑induced liver damage. The aim of the present study was to investigate whether and how n‑3 PUFAs modulate IL‑11 production during APAP‑induced liver injury. For that purpose, wild‑type (WT) and fat‑1 transgenic mice were intraperitoneally injected with APAP to induce liver injury. Serum was collected for ELISA and alanine aminotransferase assay. The hepatocytes of APAP‑injected mice were isolated for reverse transcription‑quantitative PCR and western blot analyses. For the in vitro study, primary hepatocytes isolated from WT or fat‑1 mice were stimulated with APAP. The results revealed that both endogenous and exogenous n‑3 PUFAs significantly aggravated APAP‑induced liver damage via the downregulation of STAT3 signaling. Notably, n‑3 PUFAs inhibited IL‑11 expression, but not IL‑6 expression in hepatocytes during the APAP challenge. Furthermore, it was demonstrated that limited phosphorylation of ERK1/2 and Fos‑​like‑1 (Fra‑1) expression are responsible for the n‑3 PUFA‑mediated inhibitory effect on IL‑11 production in APAP‑treated hepatocytes. It was concluded that n‑3 PUFAs inhibit IL‑11 production and further STAT3 activation in hepatocytes during APAP‑induced liver injury. Therefore, ERK1/2‑mediated Fra‑1 expression is responsible for the effect of n‑3 PUFAs on IL‑11 expression.

• Authors: Yunzhi Liu, Jingmin Lin, Yu Chen, Zhuonan Li, Jia Zhou, Xiao Lu, Zhengliang Chen, Daming Zuo
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 48 Issue 4 (Oct 2021) ISSN: 1791-244X [Electronic] Greece
• PMID: 34414450 (Publication Type: Journal Article)

Chemical References

• Fatty Acids, Omega-3
• Interleukin-11
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Acetaminophen

Topics

• Acetaminophen (adverse effects)
• Animals
• Chemical and Drug Induced Liver Injury (drug therapy, metabolism)
• Fatty Acids, Omega-3 (pharmacology)
• Hepatocytes (drug effects, metabolism)
• Interleukin-11 (metabolism)
• Liver (drug effects, metabolism)
• Liver Failure, Acute (chemically induced, drug therapy, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)