FXR Antagonist FLG249 Lowers Hepatic Triacylglycerol and Serum Cholesterol Level in High-Fat Diet-Induced Obese Mice
Farnesoid X receptor (FXR) is a nuclear receptor that regulates the synthesis and enterohepatic circulation of bile acids (BAs). It also regulates lipid and carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthes...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2024/08/13, Vol.47(8), pp.1429-1436 |
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| creator | Iguchi, Yusuke Yamashita, Yukiko Gohda, Keigo Oda, Keisuke Fujimori, Ko Sera, Yukihiro Imanaka, Tsuneo Yamaguchi, Masafumi Une, Mizuho Teno, Naoki |
| description | Farnesoid X receptor (FXR) is a nuclear receptor that regulates the synthesis and enterohepatic circulation of bile acids (BAs). It also regulates lipid and carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthesized a series of FXR antagonists and showed that oral administration of FLG249 reduced the expression of several FXR target genes in the mouse ileum. Here, we investigated the effects of FLG249 on lipid metabolism in mice fed a high-fat diet (HFD). When FLG249 was administered for 4 weeks to HFD-induced obese mice, it altered the expression of genes related to BA metabolism, ceramide synthesis and fatty acid β-oxidation, improving lipid metabolism in the liver and ileum without decreasing body weight. These findings suggest that FLG249 has the potential to be a low toxicity pharmaceutical compound and likely acts as a nonsteroidal FXR antagonist to improve lipid metabolism disorders. |
| doi_str_mv | 10.1248/bpb.b24-00311 |
| format | Article |
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It also regulates lipid and carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthesized a series of FXR antagonists and showed that oral administration of FLG249 reduced the expression of several FXR target genes in the mouse ileum. Here, we investigated the effects of FLG249 on lipid metabolism in mice fed a high-fat diet (HFD). When FLG249 was administered for 4 weeks to HFD-induced obese mice, it altered the expression of genes related to BA metabolism, ceramide synthesis and fatty acid β-oxidation, improving lipid metabolism in the liver and ileum without decreasing body weight. 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It also regulates lipid and carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthesized a series of FXR antagonists and showed that oral administration of FLG249 reduced the expression of several FXR target genes in the mouse ileum. Here, we investigated the effects of FLG249 on lipid metabolism in mice fed a high-fat diet (HFD). When FLG249 was administered for 4 weeks to HFD-induced obese mice, it altered the expression of genes related to BA metabolism, ceramide synthesis and fatty acid β-oxidation, improving lipid metabolism in the liver and ileum without decreasing body weight. These findings suggest that FLG249 has the potential to be a low toxicity pharmaceutical compound and likely acts as a nonsteroidal FXR antagonist to improve lipid metabolism disorders.</description><subject>Animals</subject><subject>Bile acids</subject><subject>Bile Acids and Salts - metabolism</subject><subject>Body weight</subject><subject>Carbohydrate metabolism</subject><subject>Cholesterol</subject><subject>Cholesterol - blood</subject><subject>cholesterol metabolism</subject><subject>Diet, High-Fat - adverse effects</subject><subject>dyslipidemia</subject><subject>farnesoid X receptor antagonist</subject><subject>Fat metabolism</subject><subject>fatty acid β-oxidation</subject><subject>High cholesterol diet</subject><subject>High fat diet</subject><subject>Ileum</subject><subject>Ileum - drug effects</subject><subject>Ileum - metabolism</subject><subject>Lipid metabolism</subject><subject>Lipid Metabolism - drug effects</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver diseases</subject><subject>Liver X receptors</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Obese</subject><subject>Obesity - blood</subject><subject>Obesity - drug therapy</subject><subject>Obesity - metabolism</subject><subject>Oral administration</subject><subject>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Toxicity</subject><subject>Triglycerides - blood</subject><issn>0918-6158</issn><issn>1347-5215</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9r2zAUx8VYWbN2x12HYJdd3D39sC0dS7o0BY9C28FuQpaeEwfHziR7I__9lKTLYRc90Pvw5b33IeQjgxvGpfpa7-qbmssMQDD2hsyYkGWWc5a_JTPQTGUFy9UleR_jBgBK4OIduRSaiZwLNSPj4ucTve1Huxr6No50Ud1zqWk1_MEQ6RJ3dmwdfQmtdftu1e0dhqGjtvf0GcO0pfP10GEcj78V_saOtj1dtqt1trAjvWtxzB56Pzn09LHGiPR76_CaXDS2i_jhtV6RH4tvL_NlVj3eP8xvq8wJDWPGdCkLreq8BGx0oxTTMtcAjQShC0RvOVjurW8E5HWN3qNyh81YWdbKF-KKfDnl7sLwa0pjmm0bHXad7XGYohGguShyKWVCP_-HboYp9Gk6IxjIkjNVQKKyE-XCEGPAxuxCu7VhbxiYgw6TdJikwxx1JP7Ta-pUb9Gf6X_3T8D8BGxiUoBnwIZ09g6PcbI06vCcY89dt7bBYC_-Ao30m_M</recordid><startdate>20240813</startdate><enddate>20240813</enddate><creator>Iguchi, Yusuke</creator><creator>Yamashita, Yukiko</creator><creator>Gohda, Keigo</creator><creator>Oda, Keisuke</creator><creator>Fujimori, Ko</creator><creator>Sera, Yukihiro</creator><creator>Imanaka, Tsuneo</creator><creator>Yamaguchi, Masafumi</creator><creator>Une, Mizuho</creator><creator>Teno, Naoki</creator><general>The Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20240813</creationdate><title>FXR Antagonist FLG249 Lowers Hepatic Triacylglycerol and Serum Cholesterol Level in High-Fat Diet-Induced Obese Mice</title><author>Iguchi, Yusuke ; Yamashita, Yukiko ; Gohda, Keigo ; Oda, Keisuke ; Fujimori, Ko ; Sera, Yukihiro ; Imanaka, Tsuneo ; Yamaguchi, Masafumi ; Une, Mizuho ; Teno, Naoki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-1974698b570ef9f881945900f40396eeda20a2dadf305bbedde8c9135177b8d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Bile acids</topic><topic>Bile Acids and Salts - metabolism</topic><topic>Body weight</topic><topic>Carbohydrate metabolism</topic><topic>Cholesterol</topic><topic>Cholesterol - blood</topic><topic>cholesterol metabolism</topic><topic>Diet, High-Fat - adverse effects</topic><topic>dyslipidemia</topic><topic>farnesoid X receptor antagonist</topic><topic>Fat metabolism</topic><topic>fatty acid β-oxidation</topic><topic>High cholesterol diet</topic><topic>High fat diet</topic><topic>Ileum</topic><topic>Ileum - drug effects</topic><topic>Ileum - metabolism</topic><topic>Lipid metabolism</topic><topic>Lipid Metabolism - drug effects</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver diseases</topic><topic>Liver X receptors</topic><topic>Male</topic><topic>Metabolic disorders</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Obese</topic><topic>Obesity - blood</topic><topic>Obesity - drug therapy</topic><topic>Obesity - metabolism</topic><topic>Oral administration</topic><topic>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Toxicity</topic><topic>Triglycerides - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iguchi, Yusuke</creatorcontrib><creatorcontrib>Yamashita, Yukiko</creatorcontrib><creatorcontrib>Gohda, Keigo</creatorcontrib><creatorcontrib>Oda, Keisuke</creatorcontrib><creatorcontrib>Fujimori, Ko</creatorcontrib><creatorcontrib>Sera, Yukihiro</creatorcontrib><creatorcontrib>Imanaka, Tsuneo</creatorcontrib><creatorcontrib>Yamaguchi, Masafumi</creatorcontrib><creatorcontrib>Une, Mizuho</creatorcontrib><creatorcontrib>Teno, Naoki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iguchi, Yusuke</au><au>Yamashita, Yukiko</au><au>Gohda, Keigo</au><au>Oda, Keisuke</au><au>Fujimori, Ko</au><au>Sera, Yukihiro</au><au>Imanaka, Tsuneo</au><au>Yamaguchi, Masafumi</au><au>Une, Mizuho</au><au>Teno, Naoki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FXR Antagonist FLG249 Lowers Hepatic Triacylglycerol and Serum Cholesterol Level in High-Fat Diet-Induced Obese Mice</atitle><jtitle>Biological & pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2024-08-13</date><risdate>2024</risdate><volume>47</volume><issue>8</issue><spage>1429</spage><epage>1436</epage><pages>1429-1436</pages><artnum>b24-00311</artnum><issn>0918-6158</issn><issn>1347-5215</issn><eissn>1347-5215</eissn><abstract>Farnesoid X receptor (FXR) is a nuclear receptor that regulates the synthesis and enterohepatic circulation of bile acids (BAs). It also regulates lipid and carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthesized a series of FXR antagonists and showed that oral administration of FLG249 reduced the expression of several FXR target genes in the mouse ileum. Here, we investigated the effects of FLG249 on lipid metabolism in mice fed a high-fat diet (HFD). When FLG249 was administered for 4 weeks to HFD-induced obese mice, it altered the expression of genes related to BA metabolism, ceramide synthesis and fatty acid β-oxidation, improving lipid metabolism in the liver and ileum without decreasing body weight. These findings suggest that FLG249 has the potential to be a low toxicity pharmaceutical compound and likely acts as a nonsteroidal FXR antagonist to improve lipid metabolism disorders.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>39135238</pmid><doi>10.1248/bpb.b24-00311</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Bile acids Bile Acids and Salts - metabolism Body weight Carbohydrate metabolism Cholesterol Cholesterol - blood cholesterol metabolism Diet, High-Fat - adverse effects dyslipidemia farnesoid X receptor antagonist Fat metabolism fatty acid β-oxidation High cholesterol diet High fat diet Ileum Ileum - drug effects Ileum - metabolism Lipid metabolism Lipid Metabolism - drug effects Liver - drug effects Liver - metabolism Liver diseases Liver X receptors Male Metabolic disorders Mice Mice, Inbred C57BL Mice, Obese Obesity - blood Obesity - drug therapy Obesity - metabolism Oral administration Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Receptors, Cytoplasmic and Nuclear - metabolism Toxicity Triglycerides - blood |
| title | FXR Antagonist FLG249 Lowers Hepatic Triacylglycerol and Serum Cholesterol Level in High-Fat Diet-Induced Obese Mice |
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