Suppression of up-regulated LXRα by silybin ameliorates experimental rheumatoid arthritis and abnormal lipid metabolism

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 LXR alpha and LXR alpha 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 LXR alpha and several key lipogenic enzymes regulated by LXR alpha, including lipoprotein lipase (LPL), cholesterol 7 alpha and 27 alpha 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 LXR alpha and abnormal lipid metabolism. Notably, activation of LXR alpha could potentiate cell inflammatory process induced by LPS through the regulation of NF-kappa B pathway, however, suppression of LXR alpha agonism by siRNA or silybin reduced the nuclear translocation of NF-kappa B as well as the induction of downstream cytokines, indicating LXR alpha agonism is the important factor for the arthritis development and could be a potential target. Conclusion: The up-regulation of LXR alpha 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 LXR alpha agonism pertains the capacity of drug target, which enables to discover and develop new drugs to treat rheumatoid arthritis with dyslipidaemia.

Automated summary

The study demonstrates that silybin can ameliorate dyslipidemia and arthritis in AIA rats through modulating lipid metabolism and suppressing the up-regulated LXR alpha, highlighting the potential of LXR alpha inhibition as a therapeutic target for rheumatoid arthritis.