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Cellular and molecular effects of silymarin on the transdifferentiation processes of LX-2 cells and its connection with lipid metabolism

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Abstract

Fibrosis process in the liver is a clinical condition established in response to chronic lesions and may be reversible in many situations. In this process, hepatic stellate cells (HSCs) activate and produce extracellular matrix compounds. During fibrosis, the lipid metabolism is also altered and contributes to the transdifferentiation of the HSCs. Thus, controlling lipid metabolism in HSCs is suggested as a method to control or reverse the fibrotic condition. In the search for therapies that modulate lipid metabolism and treat liver diseases, silymarin has been identified as a relevant natural compound to treat liver pathologies. The present study aimed to evaluate the cellular and molecular effects of silymarin in the transdifferentiation process of HSCs (LX-2) from activated phenotype to a more quiesced-like cells , also focusing on understanding the modulatory effects of silymarin on lipid metabolism of HSCs. In our analyses, 100 µM of silymarin reduced the synthesis of actin filaments in activated cells, the synthesis of the protein level of α-SMA, and other pro-fibrotic factors such as CTGF and PFGF. The concentration of 150 µM silymarin did not reverse the activation aspects of LX-2 cells. However, both evaluated concentrations of the natural compound protected the cells from the negative effects of dimethyl sulfoxide (DMSO). Furthermore, we evaluated lipid-related molecules correlated to the transdifferentiation process of LX-2, and 100 µM of silymarin demonstrated to control molecules associated with lipid metabolism such as FASN, MLYCD, ACSL4, CPTs, among others. In contrast, cellular incubation with 150 µM of silymarin increased the synthesis of long-chain fatty acids and triglycerides, regarding the higher presence of DMSO (v/v) in the solvent. In conclusion, silymarin acts as a hepatoprotective agent and modulates the pro-fibrogenic stimuli of LX-2 cells, whose effects depend on stress levels in the cellular environment.

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Acknowledgements

We thank the professor Scott L. Friedman who donated the LX-2 cell lines for this study, MAMM for StepOne™ Real-Time PCR System machine and Zanão-Filho S. for technical support.

Funding

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP—2013/21186-7, 2016/23509-4 and 2018/05286-3).

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Authors and Affiliations

  1. Laboratório de Biologia Molecular, Departamento de Biologia Geral e Aplicada, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, 13506-900, Brazil

    Caio Mateus Silva & Karen C. M. Moraes

  2. Departamento de Bioquímica E Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, USP, Ribeirão Preto, SP, Brazil

    Gustavo Duarte Ferrari

  3. Departamento de Física E Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, USP, Ribeirão Preto, SP, Brazil

    Luciane Carla Alberici

  4. Centro de Estudos de Insetos Sociais, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil

    Osmar Malaspina

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  1. Caio Mateus Silva
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  2. Gustavo Duarte Ferrari
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  3. Luciane Carla Alberici
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  5. Karen C. M. Moraes
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Correspondence to Karen C. M. Moraes.

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Silva, C.M., Ferrari, G.D., Alberici, L.C. et al. Cellular and molecular effects of silymarin on the transdifferentiation processes of LX-2 cells and its connection with lipid metabolism. Mol Cell Biochem 468, 129–142 (2020). https://doi.org/10.1007/s11010-020-03717-7

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