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<p>Metabolic steatotic liver disease (MASLD) lacks effective pharmacological therapies targeting mitochondrial dysfunction, a central driver of disease progression. We hypothesized that dapagliflozin attenuates MASLD progression by promoting an indirect systemic fasting-mimicking state, thereby proposing the hypothesis of mitochondrial restoring mitochondrial bioenergetics restoration via modulation of the SIRT1–PGC-1α signaling pathway. C57BL/6 mice were fed either a control diet or a high-fat diet, associated, respectively, with drinking water or water with 15% fructose. From the 10th to the 16th week, the animals received, by orogastric gavage, saline solution or dapagliflozin (10 mg/kg). Biochemical analyses, magnetic resonance imaging, oral glucose tolerance tests, stereology, and ultrastructural analysis of the liver, as well as Western blotting using mitochondrial markers, were performed. The study showed that exposure to the high-fat diet associated with fructose effectively mimicked the main aspects of obesity and MASLD. Intervention resulted in a reduction in adiposity without compromising muscle mass, preservation of mitochondrial integrity, improvement in mitochondrial bioenergetics, and attenuation of steatosis and hepatic cellular stress. These results suggest an association with the NT-PGC-1α–NRF1 axis; our study hypothesizes that this acts as a compensatory mechanism. These findings support further investigation of dapagliflozin as a potential therapeutic strategy for MASLD.</p>

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Dapagliflozin attenuates hepatic steatosis and induces a fasting-mimicking metabolic state in C57BL/6 mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Pericles Fabrício Gomes-Filho,
  • Carolina da Silva Valentim,
  • Cherley Borba Vieira Andrade,
  • Verônica Aiceles de Medeiros Pinto,
  • Raíssa Leal de Carvalho dos Santos Cunha,
  • Paulo Rogerio Silva de Paiva-Júnior,
  • Rebecca Roosevelt da Conceição Souza Guedes,
  • João Lucas do Céu Amparo,
  • Isalira Peroba Ramos,
  • Luciana Lontro Alves,
  • Aluana Santana Carlos,
  • Jéssica Gomes Pereira,
  • Nathália Medeiros Nehme,
  • Patrícia Cristina Lisboa,
  • Samara Cristina Ferreira-Machado,
  • Kíssila Rabelo,
  • Jorge José de Carvalho,
  • Jemima Fuentes Ribeiro da Silva

摘要

Metabolic steatotic liver disease (MASLD) lacks effective pharmacological therapies targeting mitochondrial dysfunction, a central driver of disease progression. We hypothesized that dapagliflozin attenuates MASLD progression by promoting an indirect systemic fasting-mimicking state, thereby proposing the hypothesis of mitochondrial restoring mitochondrial bioenergetics restoration via modulation of the SIRT1–PGC-1α signaling pathway. C57BL/6 mice were fed either a control diet or a high-fat diet, associated, respectively, with drinking water or water with 15% fructose. From the 10th to the 16th week, the animals received, by orogastric gavage, saline solution or dapagliflozin (10 mg/kg). Biochemical analyses, magnetic resonance imaging, oral glucose tolerance tests, stereology, and ultrastructural analysis of the liver, as well as Western blotting using mitochondrial markers, were performed. The study showed that exposure to the high-fat diet associated with fructose effectively mimicked the main aspects of obesity and MASLD. Intervention resulted in a reduction in adiposity without compromising muscle mass, preservation of mitochondrial integrity, improvement in mitochondrial bioenergetics, and attenuation of steatosis and hepatic cellular stress. These results suggest an association with the NT-PGC-1α–NRF1 axis; our study hypothesizes that this acts as a compensatory mechanism. These findings support further investigation of dapagliflozin as a potential therapeutic strategy for MASLD.