Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation
[Display omitted] 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...
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| Veröffentlicht in: | Biochemical pharmacology 2016-12, Vol.122, p.42-61 |
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| creator | Zheng, Zu-Guo Zhou, Ya-Ping Zhang, Xin Thu, Pyone Myat Xie, Zhi-Shen Lu, Chong Pang, Tao Xue, Bin Xu, Da-Qian Chen, Yan Chen, Xiao-Wei Li, Hui-Jun Xu, Xiaojun |
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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. |
| doi_str_mv | 10.1016/j.bcp.2016.10.016 |
| format | Article |
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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.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2016.10.016</identifier><identifier>PMID: 27816546</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Adenylate Kinase - genetics ; Adenylate Kinase - metabolism ; Anhydroicaritin ; Animals ; Benzopyrans - chemistry ; Benzopyrans - pharmacology ; Cell Line, Tumor ; Cell Survival - drug effects ; Gene Expression Regulation - drug effects ; Humans ; Hyperlipidemia ; Insulin Resistance ; Intracellular Signaling Peptides and Proteins - metabolism ; Membrane Proteins - metabolism ; Mice ; Molecular Structure ; Obesity ; Obesity - chemically induced ; Obesity - drug therapy ; SREBPs ; Sterol Regulatory Element Binding Proteins - genetics ; Sterol Regulatory Element Binding Proteins - metabolism ; TOR Serine-Threonine Kinases - genetics ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Biochemical pharmacology, 2016-12, Vol.122, p.42-61</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-43b22540a84eb0f661776044534c19f8732d2c65aa563d18c374eca9166e03283</citedby><cites>FETCH-LOGICAL-c396t-43b22540a84eb0f661776044534c19f8732d2c65aa563d18c374eca9166e03283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006295216303872$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27816546$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Zu-Guo</creatorcontrib><creatorcontrib>Zhou, Ya-Ping</creatorcontrib><creatorcontrib>Zhang, Xin</creatorcontrib><creatorcontrib>Thu, Pyone Myat</creatorcontrib><creatorcontrib>Xie, Zhi-Shen</creatorcontrib><creatorcontrib>Lu, Chong</creatorcontrib><creatorcontrib>Pang, Tao</creatorcontrib><creatorcontrib>Xue, Bin</creatorcontrib><creatorcontrib>Xu, Da-Qian</creatorcontrib><creatorcontrib>Chen, Yan</creatorcontrib><creatorcontrib>Chen, Xiao-Wei</creatorcontrib><creatorcontrib>Li, Hui-Jun</creatorcontrib><creatorcontrib>Xu, Xiaojun</creatorcontrib><title>Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>[Display omitted]
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.</description><subject>Adenylate Kinase - genetics</subject><subject>Adenylate Kinase - metabolism</subject><subject>Anhydroicaritin</subject><subject>Animals</subject><subject>Benzopyrans - chemistry</subject><subject>Benzopyrans - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Humans</subject><subject>Hyperlipidemia</subject><subject>Insulin Resistance</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Obesity</subject><subject>Obesity - chemically induced</subject><subject>Obesity - drug therapy</subject><subject>SREBPs</subject><subject>Sterol Regulatory Element Binding Proteins - genetics</subject><subject>Sterol Regulatory Element Binding Proteins - metabolism</subject><subject>TOR Serine-Threonine Kinases - genetics</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtP3DAUha0KVKa0P6Ab5CWbTP1InIy6oiOglZBAtF1bjn0H7ihxUtsZKWv-OB6GsmR1HzrnSOcj5CtnS864-rZdtnZcirzme5nHB7LgTS0LsVLNEVkwxlTeK3FCPsW43Z-N4h_JiagbrqpSLcjThX-cXRjQmoAJPcV-DMMOInUIqUDvJguODi1ETDM13tHHeYTQ4YgOejQvL9N1sEOTsg19nLqcE7IhJuMt0HamcRrH_InoH-jv-8sfd5Eam3BnEg7-MznemC7Cl9d5Sv5eXf5Z_yxubq9_rS9uCitXKhWlbIWoSmaaElq2UYrXtWJlWcnS8tUm9xZOWFUZUynpeGNlXYI1K64UMCkaeUrOD7m54b8JYtI9RgtdZzwMU9S8kTUTVUaTpfwgtWGIMcBGjwF7E2bNmd6z11ud2es9-_2LvXjOXuOntgf35vgPOwu-HwSQS-4Qgo4WIRNyGMAm7QZ8J_4ZR5uWgA</recordid><startdate>20161215</startdate><enddate>20161215</enddate><creator>Zheng, Zu-Guo</creator><creator>Zhou, Ya-Ping</creator><creator>Zhang, Xin</creator><creator>Thu, Pyone Myat</creator><creator>Xie, Zhi-Shen</creator><creator>Lu, Chong</creator><creator>Pang, Tao</creator><creator>Xue, Bin</creator><creator>Xu, Da-Qian</creator><creator>Chen, Yan</creator><creator>Chen, Xiao-Wei</creator><creator>Li, Hui-Jun</creator><creator>Xu, Xiaojun</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20161215</creationdate><title>Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation</title><author>Zheng, Zu-Guo ; Zhou, Ya-Ping ; Zhang, Xin ; Thu, Pyone Myat ; Xie, Zhi-Shen ; Lu, Chong ; Pang, Tao ; Xue, Bin ; Xu, Da-Qian ; Chen, Yan ; Chen, Xiao-Wei ; Li, Hui-Jun ; Xu, Xiaojun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-43b22540a84eb0f661776044534c19f8732d2c65aa563d18c374eca9166e03283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adenylate Kinase - genetics</topic><topic>Adenylate Kinase - metabolism</topic><topic>Anhydroicaritin</topic><topic>Animals</topic><topic>Benzopyrans - chemistry</topic><topic>Benzopyrans - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Humans</topic><topic>Hyperlipidemia</topic><topic>Insulin Resistance</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Obesity</topic><topic>Obesity - chemically induced</topic><topic>Obesity - drug therapy</topic><topic>SREBPs</topic><topic>Sterol Regulatory Element Binding Proteins - genetics</topic><topic>Sterol Regulatory Element Binding Proteins - metabolism</topic><topic>TOR Serine-Threonine Kinases - genetics</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Zu-Guo</creatorcontrib><creatorcontrib>Zhou, Ya-Ping</creatorcontrib><creatorcontrib>Zhang, Xin</creatorcontrib><creatorcontrib>Thu, Pyone Myat</creatorcontrib><creatorcontrib>Xie, Zhi-Shen</creatorcontrib><creatorcontrib>Lu, Chong</creatorcontrib><creatorcontrib>Pang, Tao</creatorcontrib><creatorcontrib>Xue, Bin</creatorcontrib><creatorcontrib>Xu, Da-Qian</creatorcontrib><creatorcontrib>Chen, Yan</creatorcontrib><creatorcontrib>Chen, Xiao-Wei</creatorcontrib><creatorcontrib>Li, Hui-Jun</creatorcontrib><creatorcontrib>Xu, Xiaojun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Zu-Guo</au><au>Zhou, Ya-Ping</au><au>Zhang, Xin</au><au>Thu, Pyone Myat</au><au>Xie, Zhi-Shen</au><au>Lu, Chong</au><au>Pang, Tao</au><au>Xue, Bin</au><au>Xu, Da-Qian</au><au>Chen, Yan</au><au>Chen, Xiao-Wei</au><au>Li, Hui-Jun</au><au>Xu, Xiaojun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2016-12-15</date><risdate>2016</risdate><volume>122</volume><spage>42</spage><epage>61</epage><pages>42-61</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><abstract>[Display omitted]
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.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>27816546</pmid><doi>10.1016/j.bcp.2016.10.016</doi><tpages>20</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenylate Kinase - genetics Adenylate Kinase - metabolism Anhydroicaritin Animals Benzopyrans - chemistry Benzopyrans - pharmacology Cell Line, Tumor Cell Survival - drug effects Gene Expression Regulation - drug effects Humans Hyperlipidemia Insulin Resistance Intracellular Signaling Peptides and Proteins - metabolism Membrane Proteins - metabolism Mice Molecular Structure Obesity Obesity - chemically induced Obesity - drug therapy SREBPs Sterol Regulatory Element Binding Proteins - genetics Sterol Regulatory Element Binding Proteins - metabolism TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism |
| title | Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation |
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