Gender Difference on the Effect of Omega-3 Polyunsaturated Fatty Acids on Acetaminophen-Induced Acute Liver Failure

Liu, Yunzhi; Chen, Yu; Xie, Xinghuan; Yin, Aiping; Yin, Yue; Yan, Lei; Dong, Lijun; Zhu, Zhengyumeng; Zhou, Jia; Zeng, Qingchun; Xiao, Lü; Chen, Zhengliang; Wen, Kai; Zuo, Daming

doi:10.1155/2020/8096847

Cited by 8 publications

(7 citation statements)

References 50 publications

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“…For instance, palmitic and stearic acids could be particularly harmful by promoting hepatic CYP2E1 induction [ 74 , 98 , 99 ], as previously mentioned. Furthermore, studies carried out in transgenic fat-1 mice, which endogenously convert n-6 PUFAs to n-3 PUFAs, showed that male animals were more susceptible to APAP-induced acute liver injury, possibly via a JNK-dependent mechanism and downregulation of signal transducer and activator of transcription 3 (STAT3) [ 109 , 110 ].…”

Section: Factors Modulating Apap Hepatotoxicity In Obesity and Nafldmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Begriche¹,

Penhoat²,

Bernabeu-Gentey³

et al. 2023

Livers

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The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.

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Section: Factors Modulating Apap Hepatotoxicity In Obesity and Nafldmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Begriche¹,

Penhoat²,

Bernabeu-Gentey³

et al. 2023

Livers

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“…We further validated the ability of NRH-O to image HClO in mice, and adult male mice were used as animal models. , The mice were deprived of food for 24 h before the experiment to eliminate intestinal disturbances. After 1 h of probe injection, the viscera of mice were dissected for fluorescence imaging.…”

Section: Resultsmentioning

confidence: 99%

Mitochondria-Targeted Ratiometric Chemdosimeter to Detect Hypochlorite Acid for Monitoring the Drug-Damaged Liver and Kidney

et al. 2022

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Liver and kidney injury caused by drug toxicity is a serious threat to human health. Acetaminophenol (APAP), as a common antipyretic and analgesic drug, inevitably causes injury. When it is overused, hypochlorous acid (HClO) is excessively generated due to metabolic abnormalities, resulting in the accumulation of HClO in the mitochondria of liver and kidney tissues and causing damage. In this study, we designed a series of HClO responsive ratiometric chemdosimeter NRH-X (NRH-O, NRH-S, and NRH-C) to evaluate liver and kidney injury, and found that NRH-O has a specific sensitive response to HClO. NRH-O can not only monitor the variations of endogenous HClO content of living cells by fluorescence ratio changes in the mitochondria but also detect the upregulation of HClO induced by APAP. In addition, NRH-O can also be used for anatomic diagnosis of liver and kidney injury by fluorescence ratio imaging of HClO in the tissues of inflammatory mice.

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“…WT C57BL/6J mice were obtained from the Laboratory Animal Center of Southern Medical University (Guangzhou, China). Fat-1 transgenic mice, which has been reported to carry the gene that encodes the enzyme that coverts n-6 to n-3 PUFAs endogenously (20), were hybridized with WT C57BL/6J mice, and the fat-1 genotypes of each animal were recognized as we previously described (21). A total of 79 WT C57BL/6J and 39 fat-1 mice (male, 8 weeks old, 20-25 g) were included in this study.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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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.

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Gender Difference on the Effect of Omega-3 Polyunsaturated Fatty Acids on Acetaminophen-Induced Acute Liver Failure

Cited by 8 publications

References 50 publications

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Mitochondria-Targeted Ratiometric Chemdosimeter to Detect Hypochlorite Acid for Monitoring the Drug-Damaged Liver and Kidney

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

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