School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia.
PathCelerate Ltd, Goostrey, UK.
Acta Physiol (Oxf). 2024 Oct;240(10):e14217. doi: 10.1111/apha.14217. Epub 2024 Aug 16.
Metabolic dysfunction-associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)-β agonist resmetirom/MGL-3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH.
C57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair-fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses.
MGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis.
MGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR-β agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance.
代谢相关脂肪性肝炎（MASH）是一种代谢紊乱疾病，治疗选择有限。甲状腺激素受体（THR）-β激动剂雷美替胺/MGL-3196（MGL）可增加肝脏脂肪氧化，已被批准用于治疗成人 MASH。然而，接受 MGL 治疗的患者中超过 60%未达到 MASH 缓解。因此，我们研究了 MGL 与线粒体解偶联剂 BAM15 联合治疗在 GAN 小鼠 MASH 模型中改善脂肪肝疾病结局的潜力。
C57BL/6J 雄性小鼠在 GAN 饮食喂养 38 周后进行分层和随机分组，接受包括 MGL、BAM15、MGL+BAM15 或无药物对照治疗 8 周。治疗药物混合在饮食中，通过对小鼠进行配对喂养以控制药物摄入量。通过体重、体成分、能量消耗、葡萄糖耐量、组织脂质含量和组织学分析来评估治疗效果。
与 GAN 对照组相比，MGL+BAM15 治疗在能量消耗、肝脂肪丢失、血糖控制和脂肪性肝病活动评分方面比单药治疗更有效。ALT、肝质量和血浆胆固醇的改善主要由 MGL 驱动，而体脂肪的改善主要由 BAM15 驱动。没有治疗方法改变肝纤维化。
与单药治疗相比，MGL+BAM15 治疗在 GAN 饮食喂养的小鼠中整体上具有更好的改善代谢结局的疗效。这些数据支持进一步研究 THR-β 激动剂和线粒体解偶联剂联合治疗用于治疗与脂肪肝、肥胖和胰岛素抵抗相关疾病的潜力。
