Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction‐associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways

作者：Wesam F. Farrash, Shakir Idris, Mohamed Elzubier, Elshiekh B. Khidir, Akhmed Aslam, Abdulrahman Mujalli, Riyad A. Almaimani, Ahmad A. Obaid, Mahmoud Zaki El-Readi, Mohammad A. Alobaidy, Afnan Salaka, Afnan Shakoori, Alaa M. Saleh, Faisal Minshawi, Jamil Samkari, Sallwa M. Alshehre, Bassem Refaat · 发表于：International Journal of Experimental Pathology · 年份：2024 · DOI：10.1111/iep.12519 · 被引用次数：8 · 研究领域：Liver Disease Diagnosis and Treatment、Pancreatitis Pathology and Treatment、Pancreatic function and diabetes

Abstract Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D 3 (VD 3 ) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD 3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD 3 , and SGLT2i + VD 3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD 3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H 2 O 2 ), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. ...