Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis
Imeglimin promotes glucose-stimulated insulin secretion in the pancreas in a glucose-dependent manner and inhibits gluconeogenesis in the liver. Meanwhile, imeglimin can improve mitochondrial function in hepatocytes. We used a nondiabetic metabolic dysfunction-associated steatohepatitis (MASH) model...
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2024-11-01
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| Series: | Antioxidants |
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| author | Kosuke Kaji Soichi Takeda Satoshi Iwai Norihisa Nishimura Shinya Sato Tadashi Namisaki Takemi Akahane Hitoshi Yoshiji |
| author_facet | Kosuke Kaji Soichi Takeda Satoshi Iwai Norihisa Nishimura Shinya Sato Tadashi Namisaki Takemi Akahane Hitoshi Yoshiji |
| author_sort | Kosuke Kaji |
| collection | DOAJ |
| description | Imeglimin promotes glucose-stimulated insulin secretion in the pancreas in a glucose-dependent manner and inhibits gluconeogenesis in the liver. Meanwhile, imeglimin can improve mitochondrial function in hepatocytes. We used a nondiabetic metabolic dysfunction-associated steatohepatitis (MASH) model to examine the effects of imeglimin on MASH independent of its glucose-lowering action. Mice fed a choline-deficient high-fat diet (CDA-HFD) were orally administered imeglimin (100 and 200 mg/kg twice daily), and MASH pathophysiology was evaluated after 8 weeks. Moreover, an in vitro study investigated the effects of imeglimin on palmitic acid (PA)-stimulated lipid accumulation, apoptosis, and mitochondrial dysfunction in human hepatocytes. CDA-HFD-fed mice showed hepatic steatosis, inflammation, and fibrosis without hyperglycemia. Imeglimin reduced hepatic steatosis in response to increased expression of β-oxidation-related markers. Imeglimin reduced reactive oxygen species accumulation and increased mitochondrial biogenesis in CDA-HFD-fed mice. Consequently, imeglimin suppressed hepatocyte apoptosis and decreased macrophage infiltration with reduced proinflammatory cytokine expression, suppressing hepatic fibrosis development. PA-stimulated hepatocytes induced lipogenesis, inflammatory cytokine production, and apoptosis, which were significantly suppressed by imeglimin. In mitochondrial function, imeglimin improved PA-stimulated decrease in mitochondrial membrane potential, mitochondrial complexes activity, oxygen consumption rate, and mitochondrial biogenesis marker expression. In conclusion, imeglimin could contribute to prevention of MASH progression through suppressing de novo lipogenesis and enhancing fatty acid oxidation. |
| format | Article |
| id | doaj-art-48a37e66523c4f30926e3948e683d95d |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2024-11-01 |
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| series | Antioxidants |
| spelling | doaj-art-48a37e66523c4f30926e3948e683d95d2025-08-20T02:07:57ZengMDPI AGAntioxidants2076-39212024-11-011311141510.3390/antiox13111415Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated SteatohepatitisKosuke Kaji0Soichi Takeda1Satoshi Iwai2Norihisa Nishimura3Shinya Sato4Tadashi Namisaki5Takemi Akahane6Hitoshi Yoshiji7Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanDepartment of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, JapanImeglimin promotes glucose-stimulated insulin secretion in the pancreas in a glucose-dependent manner and inhibits gluconeogenesis in the liver. Meanwhile, imeglimin can improve mitochondrial function in hepatocytes. We used a nondiabetic metabolic dysfunction-associated steatohepatitis (MASH) model to examine the effects of imeglimin on MASH independent of its glucose-lowering action. Mice fed a choline-deficient high-fat diet (CDA-HFD) were orally administered imeglimin (100 and 200 mg/kg twice daily), and MASH pathophysiology was evaluated after 8 weeks. Moreover, an in vitro study investigated the effects of imeglimin on palmitic acid (PA)-stimulated lipid accumulation, apoptosis, and mitochondrial dysfunction in human hepatocytes. CDA-HFD-fed mice showed hepatic steatosis, inflammation, and fibrosis without hyperglycemia. Imeglimin reduced hepatic steatosis in response to increased expression of β-oxidation-related markers. Imeglimin reduced reactive oxygen species accumulation and increased mitochondrial biogenesis in CDA-HFD-fed mice. Consequently, imeglimin suppressed hepatocyte apoptosis and decreased macrophage infiltration with reduced proinflammatory cytokine expression, suppressing hepatic fibrosis development. PA-stimulated hepatocytes induced lipogenesis, inflammatory cytokine production, and apoptosis, which were significantly suppressed by imeglimin. In mitochondrial function, imeglimin improved PA-stimulated decrease in mitochondrial membrane potential, mitochondrial complexes activity, oxygen consumption rate, and mitochondrial biogenesis marker expression. In conclusion, imeglimin could contribute to prevention of MASH progression through suppressing de novo lipogenesis and enhancing fatty acid oxidation.https://www.mdpi.com/2076-3921/13/11/1415imegliminhepatocytemetabolic dysfunction-associated steatohepatitisfatty acid oxidationreactive oxygen speciesmitochondrial biogenesis |
| spellingShingle | Kosuke Kaji Soichi Takeda Satoshi Iwai Norihisa Nishimura Shinya Sato Tadashi Namisaki Takemi Akahane Hitoshi Yoshiji Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis Antioxidants imeglimin hepatocyte metabolic dysfunction-associated steatohepatitis fatty acid oxidation reactive oxygen species mitochondrial biogenesis |
| title | Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis |
| title_full | Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis |
| title_fullStr | Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis |
| title_full_unstemmed | Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis |
| title_short | Imeglimin Halts Liver Damage by Improving Mitochondrial Dysfunction in a Nondiabetic Male Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis |
| title_sort | imeglimin halts liver damage by improving mitochondrial dysfunction in a nondiabetic male mouse model of metabolic dysfunction associated steatohepatitis |
| topic | imeglimin hepatocyte metabolic dysfunction-associated steatohepatitis fatty acid oxidation reactive oxygen species mitochondrial biogenesis |
| url | https://www.mdpi.com/2076-3921/13/11/1415 |
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