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

ABSTRACT: 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 (Ca2+) 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 ([Ca2+]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 [Ca2+]c. By computational virtual docking analysis and biochemical assays, Mat was shown to influence [Ca2+]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.

SUBMITTER: Gao X

PROVIDER: S-EPMC6245862 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Gao Xiaobo X Guo Shun S Zhang Song S Liu An A Shi Lei L Zhang Yan Y

Journal of translational medicine 20181120 1

<h4>Background</h4>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<sup>2+</sup>) 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.<h4 ...[more]

PMID: 30458883

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Project description:BackgroundPorcine circovirus type 2 (PCV2) is an important and common DNA virus that infect pig and can cause immunosuppression and induce apoptosis in the infected cells. To escape the host immune system, PCV2 constantly builds up complex mechanisms or mutates genes, and that is why it is difficult to eradicate complex PCV2 infection by relying on vaccines and single compound. At present, there is few literature reports on the effective prevention and treatment of PCV2 infection by a combination of two or more compounds. Previously, we have demonstrated the anti-PCV2 effect of Matrine in vitro, but its mechanism has not been further evaluated. Literatures have proven that Osthole has a variety of pharmacological activities, and we tested the ability of Osthole to inhibit PCV2 replication in cell culture. Therefore, this study explored the synergistic antiviral effect of Matrine combined with Osthole and their synergistic anti-apoptotic mechanism.ResultsOsthole alone had an anti-PCV2 effect, and then its synergistic anti-PCV2 effect of Osthole and Matrine was better than that of Matrine or Osthole alone as demonstrated by qRT-PCR, IFA and Western blotting results. The anti-apoptotic mechanism of these two compounds by inducing the PERK pathway by PCV2 was elucidated through Annexin V-FITC/PI, JC-1 and Western blotting. Matrine and Osthole combination could inhibit the expression of Cap in Cap-transfected PK-15 cells, thus inhibiting Cap-induced PERK apoptosis. Ribavirin was used as a positive control.ConclusionsThe combination of Osthole and Matrine had the synergistic effect of anti-PCV2 infection by directly inhibiting the expression of PCV2 Cap protein. The combination of these two compounds also inhibited PERK apoptosis induced by PCV2 Cap protein, possibly by regulating the level of GRP78. The results formed a base for further studies on the mechanism of anti-PCV2 in vivo using Matrine and Osthole combination and developing new anti-PCV2 compounds with Cap and GRP78 as therapeutic targets.

Dataset Information

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

Publications

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

Similar Datasets

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