Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation
Abstract Current research efforts in polymer and nanotechnology applications are primarily focused on cargo delivery to enhance the therapeutic index, with limited attention being paid to self‐molecularly targeted nanoparticles, which may also exhibit significant therapeutic potential. Long‐term and...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202408906 |
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| author | Yunfei Zhao Ke Hu Fangliang Wang Lulu Zhao Yu Su Jun Chen Gang Zou Liming Yang Li Wei Mengjiao Deng Yunyu He Ping Wang Xiong Z Ruan Yaxi Chen Chao Yu |
| author_facet | Yunfei Zhao Ke Hu Fangliang Wang Lulu Zhao Yu Su Jun Chen Gang Zou Liming Yang Li Wei Mengjiao Deng Yunyu He Ping Wang Xiong Z Ruan Yaxi Chen Chao Yu |
| author_sort | Yunfei Zhao |
| collection | DOAJ |
| description | Abstract Current research efforts in polymer and nanotechnology applications are primarily focused on cargo delivery to enhance the therapeutic index, with limited attention being paid to self‐molecularly targeted nanoparticles, which may also exhibit significant therapeutic potential. Long‐term and anomalous lipid accumulation in the liver is a highly relevant factor contributing to liver diseases. However, the development of the reliable medications and their pharmacological mechanisms remain insufficient. Herein, a polyguanide nanoinhibitors (PGNI) depot is constructed by copolymerizing biguanide derivatives in different proportions onto prepolymers. The nanoinhibitors for their ability to ameliorate lipid accumulation in vitro and in vivo is screened, and subsequently demonstrated that covalently polymeric guanidine chains exhibit superior efficacy in ameliorating hepatic lipid accumulation via heterogeneous mechanisms compared to small‐molecule guanidine. It is found that PGNIs stabilize guanidine metabolism in the liver, preferably for biosafety. More importantly, PGNI is ingested and localized in hepatocyte lysosomes and is locked to interact with vesicular adenosine triphosphatase (V‐ATPase) on lysosomes, leading to the inhibition of V‐ATPase and lysosomal acidification, thereby activating the AMPK pathway, reducing fatty acid synthesis, and enhancing lipolysis and fatty acid oxidation. These results imply that polymer‐formed nanoparticles can serve as targeted inhibitors, offering a novel approach for therapeutic applications. |
| format | Article |
| id | doaj-art-1b9333090d514794afdbfa4f4fd5dd1f |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-1b9333090d514794afdbfa4f4fd5dd1f2025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202408906Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid AccumulationYunfei Zhao0Ke Hu1Fangliang Wang2Lulu Zhao3Yu Su4Jun Chen5Gang Zou6Liming Yang7Li Wei8Mengjiao Deng9Yunyu He10Ping Wang11Xiong Z Ruan12Yaxi Chen13Chao Yu14Chongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaCentre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaCentre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaCentre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaCentre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaCentre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaCentre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Institute for Viral Hepatitis Department of Infectious Diseases the Second Affiliated Hospital Chongqing Medical University Chongqing 400016 P. R. ChinaChongqing Medical University College of Pharmacy Chongqing Key Laboratory for Pharmaceutical Metabolism Research Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center Chongqing 400016 P. R. ChinaAbstract Current research efforts in polymer and nanotechnology applications are primarily focused on cargo delivery to enhance the therapeutic index, with limited attention being paid to self‐molecularly targeted nanoparticles, which may also exhibit significant therapeutic potential. Long‐term and anomalous lipid accumulation in the liver is a highly relevant factor contributing to liver diseases. However, the development of the reliable medications and their pharmacological mechanisms remain insufficient. Herein, a polyguanide nanoinhibitors (PGNI) depot is constructed by copolymerizing biguanide derivatives in different proportions onto prepolymers. The nanoinhibitors for their ability to ameliorate lipid accumulation in vitro and in vivo is screened, and subsequently demonstrated that covalently polymeric guanidine chains exhibit superior efficacy in ameliorating hepatic lipid accumulation via heterogeneous mechanisms compared to small‐molecule guanidine. It is found that PGNIs stabilize guanidine metabolism in the liver, preferably for biosafety. More importantly, PGNI is ingested and localized in hepatocyte lysosomes and is locked to interact with vesicular adenosine triphosphatase (V‐ATPase) on lysosomes, leading to the inhibition of V‐ATPase and lysosomal acidification, thereby activating the AMPK pathway, reducing fatty acid synthesis, and enhancing lipolysis and fatty acid oxidation. These results imply that polymer‐formed nanoparticles can serve as targeted inhibitors, offering a novel approach for therapeutic applications.https://doi.org/10.1002/advs.202408906AMPKliver lipid accumulationlysosomepolyguanide nanoinhibitor (PGNIs)V‐ATPase |
| spellingShingle | Yunfei Zhao Ke Hu Fangliang Wang Lulu Zhao Yu Su Jun Chen Gang Zou Liming Yang Li Wei Mengjiao Deng Yunyu He Ping Wang Xiong Z Ruan Yaxi Chen Chao Yu Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation Advanced Science AMPK liver lipid accumulation lysosome polyguanide nanoinhibitor (PGNIs) V‐ATPase |
| title | Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation |
| title_full | Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation |
| title_fullStr | Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation |
| title_full_unstemmed | Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation |
| title_short | Guanidine‐Derived Polymeric Nanoinhibitors Target the Lysosomal V‐ATPase and Activate AMPK Pathway to Ameliorate Liver Lipid Accumulation |
| title_sort | guanidine derived polymeric nanoinhibitors target the lysosomal v atpase and activate ampk pathway to ameliorate liver lipid accumulation |
| topic | AMPK liver lipid accumulation lysosome polyguanide nanoinhibitor (PGNIs) V‐ATPase |
| url | https://doi.org/10.1002/advs.202408906 |
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