Hypolipidemic effect of SIPI-7623, a derivative of an extract from oriental wormwood, through farnesoid X receptor antagonism.
10.1016/S1875-5364(18)30094-3
- Author:
Yi-Fang DENG
1
;
Xiao-Ling HUANG
1
;
Mei SU
2
;
Peng-Xia YU
1
;
Zhen ZHANG
1
;
Quan-Hai LIU
1
;
Guo-Ping WANG
3
;
Min-Yu LIU
4
Author Information
1. Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China.
2. Jiangsu Carephar Pharmaceutical Co., Ltd., Nanjing 210016, China.
3. Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China. Electronic address: 13501701009@139.com.
4. Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China. Electronic address: liuminmyu_lmy@163.com.
- Publication Type:Journal Article
- Keywords:
Bile acid enterohepatic circulation;
Cholesterol-7-alpha-hydroxylase;
Farnesoid X receptor antagonist;
Hypolipidemic;
Sterol-regulatory element-binding protein 1c
- MeSH:
Animals;
Artemisia;
chemistry;
Atherosclerosis;
drug therapy;
genetics;
metabolism;
Cholesterol;
metabolism;
Cholesterol 7-alpha-Hydroxylase;
genetics;
metabolism;
Drugs, Chinese Herbal;
administration & dosage;
Humans;
Hyperlipidemias;
drug therapy;
genetics;
metabolism;
Hypolipidemic Agents;
administration & dosage;
Liver;
drug effects;
metabolism;
Male;
Rabbits;
Rats;
Rats, Sprague-Dawley;
Receptors, Cytoplasmic and Nuclear;
antagonists & inhibitors;
genetics;
metabolism;
Sterol Regulatory Element Binding Protein 1;
genetics;
metabolism;
Triglycerides;
metabolism
- From:
Chinese Journal of Natural Medicines (English Ed.)
2018;16(8):572-579
- CountryChina
- Language:English
-
Abstract:
Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.
