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Melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response

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Abstract

Melatonin, an indole neurohormone secreted mainly by the pineal gland, has been found to be involved in a variety of liver diseases. However, the underlying mechanism by which melatonin ameliorates cholestatic liver injury is not fully understood. In this study, we investigated the mechanism by which melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response. We measured the levels of serum melatonin in patients with obstructive cholestasis (n = 9), patients with primary biliary cholangitis (PBC) (n = 11), and control patients (n = 7). We performed experiments with C57BL/6 J mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and melatonin to verify the role of melatonin in the mouse model of cholestasis. Primary mouse hepatocytes were used for in vitro studies to study the mechanisms of action of melatonin in cholestasis. The levels of serum melatonin were markedly increased and negatively correlated with serum markers of liver injury in cholestatic patients. As expected, oral administration of melatonin significantly attenuated cholestasis-induced liver inflammation and fibrosis in 0.1% DDC diet-fed mice. Further mechanistic studies in cholestatic mice and primary hepatocytes revealed that melatonin reduced the conjugate BA-stimulated expression of cytokines (e.g. Ccl2, Tnfα, and Il6) through the ERK/Egr1 signalling pathway in these models. The levels of serum melatonin are significantly elevated in cholestatic patients. Melatonin treatment ameliorates cholestatic liver injury by suppressing the inflammatory response in vivo and in vitro. Therefore, melatonin is a promising novel therapeutic strategy for cholestasis.

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Data availability

The dataset used for the current study is available from the corresponding author on reasonable request.

Abbreviations

BDL:

Bile duct ligation

ERK:

Extracellular signal-regulated kinase

KO:

Knockout

mRNA:

Messenger RNA

PBC:

Primary biliary cholangitis

PCR:

Polymerase chain reaction

TCA:

Taurocholate acid

TDCA:

Taurodeoxycholic acid

WT:

Wild type

DDC:

3,5-Diethoxycarbonyl-1,4-dihydrocollidine

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Acknowledgements

We would like to thank our team members (Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital to Third Military Medical University, Chongqing, China) for their technical assistance.

Funding

This work was supported by National Natural Science Foundation of China (81922012, 82000545) and Natural Science Foundation of Southwest Hospital (XZ-2019-505-071).

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Authors and Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Ya Tan, Nan Zhao, Qiaoling Xie, Ziqian Xu, Jin Chai, Xiaoxun Zhang & Yan Li

  2. Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Ya Tan, Nan Zhao, Qiaoling Xie, Ziqian Xu, Jin Chai, Xiaoxun Zhang & Yan Li

  3. Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Ya Tan, Nan Zhao, Qiaoling Xie, Ziqian Xu, Jin Chai, Xiaoxun Zhang & Yan Li

  4. Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Ya Tan, Nan Zhao, Qiaoling Xie, Ziqian Xu, Jin Chai, Xiaoxun Zhang & Yan Li

Authors
  1. Ya Tan
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Contributions

JC and XZ conceived the experiments; YT, JC and XZ wrote the paper; YT and NZ performed the experiments; YL, YT and QX analysed the data; QX, ZX and YL contributed to reagents/materials/analysis tools; YL and XZ designed the experiments.

Corresponding authors

Correspondence to Jin Chai, Xiaoxun Zhang or Yan Li.

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Conflict of interest

The authors disclose no conflicts.

Ethical approval

We recruited patients from the Institute of Hepatobiliary Surgery and Department of Gastroenterology, The First Affiliated Hospital to Third Military Medical University (Chongqing, China). The study protocol was approved by the Institutional Ethics Review Board of The First Affiliated Hospital to Third Military Medical University, Chongqing, China (B-KY2021038). All animal studies and protocols were approved by the Institutional Animal Care and Use Committee of Third Military Medical University (AMUWEC20201580).

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Tan, Y., Zhao, N., Xie, Q. et al. Melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response. Mol Cell Biochem 478, 2527–2537 (2023). https://doi.org/10.1007/s11010-023-04682-7

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