Hupa-Breier Katharina Luise, Dywicki Janine, Hartleben Björn, Wellhöner Freya, Heidrich Benjamin, Taubert Richard, Mederacke Young-Seon Elisabeth, Lieber Maren, Iordanidis Konstantinos, Manns Michael P, Wedemeyer Heiner, Hardtke-Wolenski Matthias, Jaeckel Elmar
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
Department of Pathology, Hannover Medical School, 30625 Hannover, Germany.
Biomedicines. 2021 Mar 30;9(4):353. doi: 10.3390/biomedicines9040353.
Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6C and CD4Foxp3 T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.
葡萄糖稳态失调在非酒精性脂肪性肝炎（NASH）的发病机制中起主要作用，因为它会激活促炎和促纤维化过程。诸如胰高血糖素样肽-1（GLP-1）激动剂或钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂等降糖治疗对糖尿病患者NASH的有益作用已得到研究。然而，它们在非糖尿病背景下对NASH的影响仍不清楚。为此，我们在非糖尿病NASH小鼠模型中研究了长效GLP-1激动剂度拉糖肽和SGLT-2抑制剂恩格列净及其联合用药的效果。C57BL/6小鼠接受富含胆固醇的高脂高果糖（HFHC）饮食16周。饮食12周后，小鼠分别接受度拉糖肽、恩格列净或其联合用药治疗。单独使用度拉糖肽及其与恩格列净联合使用均导致体重显著减轻、改善葡萄糖稳态并减少促炎和促纤维化途径。度拉糖肽与恩格列净联合使用进一步降低了单核细胞趋化蛋白-1（MCP-1）和CD4 + Foxp3 + T细胞。单独使用恩格列净治疗未显示出有益效果。虽然度拉糖肽或其与恩格列净联合使用对肝脂肪变性没有明显影响，但这些数据表明度拉糖肽及其与恩格列净联合使用在非糖尿病背景下具有明显的抗炎作用，这可能对NASH的进一步治疗具有重要意义。
