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Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway

BACKGROUND: Endoplasmic reticulum (ER) stress, which can promote lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Calcium (Ca(2+)) homeostasis is considered to play a key role in ER stress. Matrine (Mat) has be...

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Autores principales: Gao, Xiaobo, Guo, Shun, Zhang, Song, Liu, An, Shi, Lei, Zhang, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245862/
https://www.ncbi.nlm.nih.gov/pubmed/30458883
http://dx.doi.org/10.1186/s12967-018-1685-2
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author Gao, Xiaobo
Guo, Shun
Zhang, Song
Liu, An
Shi, Lei
Zhang, Yan
author_facet Gao, Xiaobo
Guo, Shun
Zhang, Song
Liu, An
Shi, Lei
Zhang, Yan
author_sort Gao, Xiaobo
collection PubMed
description BACKGROUND: Endoplasmic reticulum (ER) stress, which can promote lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Calcium (Ca(2+)) homeostasis is considered to play a key role in ER stress. Matrine (Mat) has been applied for the treatment of hepatitis B, but its effect on NAFLD is still unknown, and there is no unified view of Mat on the regulation of ER stress in the previous literature. METHODS: The pharmacological effects were studied in high-fat-diet or methionine–choline-deficient diet induced C57BL/6J mice models and in palmitic acid (PA) induced L02 human liver cell model. Calcium fluorescence experiments, computational virtual docking analysis and biochemical assays were used in identifying the locus of Mat. RESULTS: The results showed that Mat-treated mice were more resistant to steatosis in the liver than vehicle-treated mice and that Mat significantly reduced hepatic inflammation, lipid peroxides. The beneficial effect of Mat was associated with suppressing ER stress and restoring mitochondrial dysfunction. Additionally, Mat decreased the PA-induced lipid accumulation, ER stress and cytosolic calcium level ([Ca(2+)](c)) in hepatocyte cell lines in low and middle dose. However, the high dose Mat did not show satisfactory results in cell model. Calcium fluorescence experiments showed that Mat was able to regulate [Ca(2+)](c). By computational virtual docking analysis and biochemical assays, Mat was shown to influence [Ca(2+)](c) via direct inhibition of SERCA. CONCLUSIONS: The results showed that the bi-directional regulation of Mat to endoplasmic reticulum at different doses was based on the inhibition of SERCA. In addition, the results also provide a theoretical basis for Mat as a potential therapeutic strategy in NAFLD/NASH. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1685-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-62458622018-11-26 Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway Gao, Xiaobo Guo, Shun Zhang, Song Liu, An Shi, Lei Zhang, Yan J Transl Med Research BACKGROUND: Endoplasmic reticulum (ER) stress, which can promote lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Calcium (Ca(2+)) homeostasis is considered to play a key role in ER stress. Matrine (Mat) has been applied for the treatment of hepatitis B, but its effect on NAFLD is still unknown, and there is no unified view of Mat on the regulation of ER stress in the previous literature. METHODS: The pharmacological effects were studied in high-fat-diet or methionine–choline-deficient diet induced C57BL/6J mice models and in palmitic acid (PA) induced L02 human liver cell model. Calcium fluorescence experiments, computational virtual docking analysis and biochemical assays were used in identifying the locus of Mat. RESULTS: The results showed that Mat-treated mice were more resistant to steatosis in the liver than vehicle-treated mice and that Mat significantly reduced hepatic inflammation, lipid peroxides. The beneficial effect of Mat was associated with suppressing ER stress and restoring mitochondrial dysfunction. Additionally, Mat decreased the PA-induced lipid accumulation, ER stress and cytosolic calcium level ([Ca(2+)](c)) in hepatocyte cell lines in low and middle dose. However, the high dose Mat did not show satisfactory results in cell model. Calcium fluorescence experiments showed that Mat was able to regulate [Ca(2+)](c). By computational virtual docking analysis and biochemical assays, Mat was shown to influence [Ca(2+)](c) via direct inhibition of SERCA. CONCLUSIONS: The results showed that the bi-directional regulation of Mat to endoplasmic reticulum at different doses was based on the inhibition of SERCA. In addition, the results also provide a theoretical basis for Mat as a potential therapeutic strategy in NAFLD/NASH. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1685-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-20 /pmc/articles/PMC6245862/ /pubmed/30458883 http://dx.doi.org/10.1186/s12967-018-1685-2 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Gao, Xiaobo
Guo, Shun
Zhang, Song
Liu, An
Shi, Lei
Zhang, Yan
Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway
title Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway
title_full Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway
title_fullStr Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway
title_full_unstemmed Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway
title_short Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway
title_sort matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating serca pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245862/
https://www.ncbi.nlm.nih.gov/pubmed/30458883
http://dx.doi.org/10.1186/s12967-018-1685-2
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