Suppression of up-regulated LXRα by silybin ameliorates experimental rheumatoid arthritis and abnormal lipid metabolism
| Autor: | Ying Xie, Senling Feng, Zhongqiu Liu, Hua Zhou, Chu-Tian Mai, Liang Liu, Yan-Fang Zheng, Hui Wang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
CD36 Pharmaceutical Science Arthritis Pharmacology Cell Line Arthritis Rheumatoid Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Adipocyte Drug Discovery Medicine Animals Humans 030304 developmental biology Dyslipidemias Liver X Receptors 0303 health sciences Lipoprotein lipase biology business.industry Lipogenesis NF-kappa B Lipid metabolism medicine.disease Lipid Metabolism Arthritis Experimental Enzymes Up-Regulation Complementary and alternative medicine chemistry Gene Expression Regulation Liver 030220 oncology & carcinogenesis Silybin biology.protein Hepatocytes Molecular Medicine Cytokines business Dyslipidemia |
| Zdroj: | Phytomedicine : international journal of phytotherapy and phytopharmacology. 80 |
| ISSN: | 1618-095X |
| Popis: | Background As dysregulation of immunometabolism plays a key role in the immunological diseases, dyslipidemia frequently observed in rheumatoid arthritis (RA) patients (60%) is associated with the disease activity and has been considered as the potential target of anti-inflammatory strategy. However, targeting of metabolic events to develop novel anti-inflammatory therapeutics are far from clear as well as the mechanism of dyslipidemia in RA. Purpose To explore the therapeutic potential and mechanisms of silybin again RA through the regulation of lipid metabolism. Methods Adjuvant-induced arthritis (AIA) rat model was used to examine the effects of silybin on modulating dysregulated lipid metabolism and arthritis. Metabolomics, docking technology, and biochemical methods such as western blots, qRT-PCR, immunofluorescence staining were performed to understanding the underlying mechanisms. Moreover, knock-down of LXRα and LXRα agonist were used on LO2 cell lines to understand the action of silybin. Results We are the first to demonstrate that silybin can ameliorate dyslipidemia and arthritis in AIA rats. Overexpression of LXRα and several key lipogenic enzymes regulated by LXRα, including lipoprotein lipase (LPL), cholesterol 7α and 27α hydroxylase (CYP7A, CYP27A), adipocyte fatty acid-binding protein (aP2/FABP4) and fatty acid translocase (CD36/FAT), were observed in AIA rats, which mostly accounted for dyslipidemia during arthritis development. Metabolomics, docking technology, and biochemical results indicated that anti-arthritis effects of silybin related to suppressing the up-regulated LXRα and abnormal lipid metabolism. Notably, activation of LXRα could potentiate cell inflammatory process induced by LPS through the regulation of NF-κB pathway, however, suppression of LXRα agonism by siRNA or silybin reduced the nuclear translocation of NF-κB as well as the induction of downstream cytokines, indicating LXRα agonism is the important factor for the arthritis development and could be a potential target. Conclusion The up-regulation of LXRα can activate lipogenesis enzymes to worsen the inflammatory process in AIA rats as well as the development of dyslipidemia, therefore, rectifying lipid disorder via suppression of LXRα agonism pertains the capacity of drug target, which enables to discover and develop new drugs to treat rheumatoid arthritis with dyslipidaemia. |
| Databáze: | OpenAIRE |
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