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

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• 作者：Zu-Guo Zheng^a ; ¹ ; Ya-Ping Zhou^a ; ¹ ; Xin Zhang^a ; Pyone Myat Thu^a ; Zhi-Shen Xie^a ; Chong Lu^a ; Tao Pang^a ; ^b ; Bin Xue^c ; Da-Qian Xu^d ; Yan Chen^d ; Xiao-Wei Chen^e ; Hui-Jun Li^a ; ^{cpuli@163.com} ; Xiaojun Xu^a ; ^b ; ^{xiaojunxu2000@163.com}
• 关键词：MetS ; metabolic syndrome ; T2DM ; type 2 diabetes mellitus ; SREBPs ; sterol regulatory element-binding proteins ; SCAP ; SREBP cleavage-activating protein ; Insigs ; insulin-induced genes ; COP II ; coated protein II ; S1P ; site-1 protease-1 ; S2P ; site-2 protease ; 25-HC ; 25-hydroxycholesterol ; TC ; total cholesterol ; TG ; triglyceride ; LDL-C ; low-density lipoprotein cholesterol ; HDL-C ; high-density lipoprotein cholesterol ; WD ; western-type diet ; WAT ; white adipose tissue ; BAT ; brown adipose tissue ; LKB1 ; li
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：122
• 期：Complete
• 页码：42-61
• 全文大小：8523 K
• 卷排序：122

文摘

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.