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

Abstract

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.

• Authors: Ying Xie, Sen-Ling Feng, Chu-Tian Mai, Yan-Fang Zheng, Hui Wang, Zhong-Qiu Liu, Hua Zhou, Liang Liu
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 80 Pg. 153339 (Jan 2021) ISSN: 1618-095X [Electronic] Germany
• PMID: 33038868 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier GmbH. All rights reserved.

Chemical References

• Cytokines
• Enzymes
• Liver X Receptors
• NF-kappa B
• Nr1h3 protein, rat
• Silybin

Topics

• Animals
• Arthritis, Experimental (drug therapy, metabolism)
• Arthritis, Rheumatoid (drug therapy)
• Cell Line
• Cytokines (metabolism)
• Dyslipidemias (drug therapy)
• Enzymes (metabolism)
• Gene Expression Regulation (drug effects)
• Hepatocytes (drug effects)
• Humans
• Lipid Metabolism (drug effects)
• Lipogenesis (drug effects, physiology)
• Liver (drug effects, metabolism)
• Liver X Receptors (antagonists & inhibitors, genetics, metabolism)
• Male
• NF-kappa B (metabolism)
• Rats, Sprague-Dawley
• Silybin (pharmacology)
• Up-Regulation (drug effects)