2. Academic Validation
  3. Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation

Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation

  • Biochem Pharmacol. 2016 Dec 15;122:42-61. doi: 10.1016/j.bcp.2016.10.016.
Zu-Guo Zheng 1,  Ya-Ping Zhou 1,  Xin Zhang 1,  Pyone Myat Thu 1,  Zhi-Shen Xie 1,  Chong Lu 1,  Tao Pang 2,  Bin Xue 3,  Da-Qian Xu 4,  Yan Chen 4,  Xiao-Wei Chen 5,  Hui-Jun Li 6,  Xiaojun Xu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China.
  • 2 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.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine and School of Medicine, Nanjing University, 210093 Nanjing, Jiangsu, China.
  • 4 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences, 200031 Shanghai, China.
  • 5 Institute of Molecular Medicine, Peking University, 100871 Beijing, China.
  • 6 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China. Electronic address: cpuli@163.com.
  • 7 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.
PMID: 27816546 DOI: 10.1016/j.bcp.2016.10.016
Abstract

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.

Keywords

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.

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