Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation.
SREBPs play important roles in the regulation of lipid metabolism, and are closely related to the occurrence and development of many metabolic diseases. Small molecular inhibitors of SERBPs are important tools in developing efficient treatment of metabolic diseases. However, there are no listing drug targeting SREBPs. Therefore, there is an urgent need to develop highly specific small molecules that inhibit SREBPs. In this study, using a hepatocyte-based high-throughput screening, we identified anhydroicaritin (AHI) as a novel inhibitor of SREBPs. HepG2, HL-7702, and human primary hepatocytes were used to verify the effects of AHI. We explored the mechanism by which AHI blocks the binding of SCAP/SREBPs complex with Sec23α/24D via regulating LKB1/AMPK/mTOR pathway. AHI reduced liver cell lipid level by preventing de novo lipogenesis. In diet induced obese mice, AHI ameliorated obesity, insulin resistance, fatty accumulation in liver and hyperlipemia. In conclusion, AHI improves diet-induced obesity and alleviates insulin resistance by suppressing SREBPs maturation which is dependent on LKB1/AMPK/mTOR pathway. Thus, AHI can serve as a leading compound for pharmacological control of metabolic diseases.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
Zu-Guo
ZG
Zheng
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
Ya-Ping
YP
Zhou
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
Xin
X
Zhang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
Pyone Myat
PM
Thu
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
Zhi-Shen
ZS
Xie
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
Chong
C
Lu
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
Tao
T
Pang
State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine and School of Medicine, Nanjing University, 210093 Nanjing, Jiangsu, China.
Bin
B
Xue
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences, 200031 Shanghai, China.
Da-Qian
DQ
Xu
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences, 200031 Shanghai, China.
Yan
Y
Chen
Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
Xiao-Wei
XW
Chen
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China. Electronic address: cpuli@163.com.
Hui-Jun
HJ
Li
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China. Electronic address: xiaojunxu2000@163.com.
Xiaojun
X
Xu
D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009765:Obesity / Q000139:chemically induced* / Q000188:drug therapy*; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D001578:Benzopyrans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; C578157:anhydroicaritin; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
25-Hydroxycholesterol (PubChem CID: 65094); 3,5-Dihydroxy-4′-methoxy-6″,6″-dimethyl-4″,5″-dihydropyrano(2″,3″:7,8)-flavone (PubChem CID: 14583584); Anhydroicaritin; Anhydroicaritin (PubChem CID: 5318980); Compound C (PubChem CID: 11524144); Epimedin A (PubChem CID: 24721194); Epimedin B (PubChem CID: 5748393); Epimedin C (PubChem CID: 5748394); Hyperlipidemia; Icariin (PubChem CID: 5318997); Icarisid I (PubChem CID: 5745470); Icarisid II (PubChem CID: 5488822); Icaritin (PubChem CID: 14427423); Insulin resistance; Isoanhydroicaritin (PubChem CID: 5322079); Lovastatin (PubChem CID: 53232); MHY1485 (PubChem CID: 2834965); Obesity; Rapamycin (PubChem CID: 5284616); SREBPs