通过促进代谢、氧化应激和炎症通路的调节,增强empagliflozin和维生素D双重疗法对小鼠代谢功能障碍相关性脂肪性肝炎的保肝作用。

IF 1.8 4区 医学 Q3 PATHOLOGY International Journal of Experimental Pathology Pub Date : 2024-10-13 DOI:10.1111/iep.12519
Wesam F. Farrash, Shakir Idris, Mohamed E. Elzubier, Elshiekh B. A. Khidir, Akhmed Aslam, Abdulrahman Mujalli, Riyad A. Almaimani, Ahmad A. Obaid, Mahmoud Z. El-Readi, Mohammad A. Alobaidy, Afnan Salaka, Afnan M. Shakoori, Alaa M. Saleh, Faisal Minshawi, Jamil A. Samkari, Sallwa M. Alshehre, Bassem Refaat
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引用次数: 0

摘要

尽管钠-葡萄糖共转运体-2抑制剂(SGLT2i)或维生素D3(VD3)的单一治疗可抑制糖尿病患者代谢功能障碍相关性脂肪性肝炎(MASH)的发展,但之前尚未探讨过它们的联合治疗。因此,本研究探讨了 SGLT2i(empagliflozin)和/或 VD3 对 2 型糖尿病小鼠 MASH 的保肝作用。40 只小鼠被分为阴性(NC)和阳性(PC)对照组、SGLT2i 组、VD3 组和 SGLT2i + VD3 组。除 NC 组外,所有动物均接受高果糖/高脂肪饮食(8 周),然后诱发糖尿病。然后,糖尿病小鼠接受另一周期的高果糖/高脂肪饮食(4 周),接着接受 8 周的 SGLT2i(5.1 毫克/千克/天)和/或 VD3(410 IU/Kg/天)治疗(5 次/周)。PC 组表现为高血糖、血脂异常、肝酶升高、非酒精性脂肪肝活动评分(NAS)增加并伴有纤维化。PC 组的肝糖转运分子(SGLT2)、脂肪生成(SREBP-1/PPARγ)、氧化应激(MDA/H2O2)、炎症(IL1β/IL6/TNF-α)、纤维化(TGF-β1/α-SMA)和细胞凋亡(TUNEL/Caspase-3)标记物以及 PI3K/AKT/mTOR 通路均有所增加。相反,PC 组的肝脏胰岛素依赖性葡萄糖转运体(GLUT4)、脂肪分解(PPARα/INSIG1)、抗氧化(GSH/GPx1/SOD1/CAT)和抗炎(IL-10)分子以及 PI3K/AKT/mTOR 通路抑制剂(PTEN)减少。虽然SGLT2i单药治疗的效果优于VD3,但它们的联合治疗对高血糖、血脂异常和肝纤维化的缓解效果最好,对肝葡萄糖转运和脂质调节分子、PI3K/AKT/mTOR通路以及氧化应激、炎症、肝纤维化和细胞凋亡标志物的调节作用最强。这项研究首次揭示了 SGLT2i 和 VD3 联合疗法对糖尿病诱导的 MASH 有增强的肝脏保护作用,这可能是通过增强代谢控制和调节肝脏 PI3K/AKT/mTOR、抗炎、抗氧化和抗纤维化途径实现的。
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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

Although single treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) or vitamin D3 (VD3) 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 VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 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 VD3 (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/H2O2), 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. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose-transporting and lipid-regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co-therapy against diabetes-induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti-inflammatory, anti-oxidative, and anti-fibrotic pathways.

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来源期刊
CiteScore
4.50
自引率
3.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: Experimental Pathology encompasses the use of multidisciplinary scientific techniques to investigate the pathogenesis and progression of pathologic processes. The International Journal of Experimental Pathology - IJEP - publishes papers which afford new and imaginative insights into the basic mechanisms underlying human disease, including in vitro work, animal models, and clinical research. Aiming to report on work that addresses the common theme of mechanism at a cellular and molecular level, IJEP publishes both original experimental investigations and review articles. Recent themes for review series have covered topics as diverse as "Viruses and Cancer", "Granulomatous Diseases", "Stem cells" and "Cardiovascular Pathology".
期刊最新文献
Issue Information Histomorphometric analysis of excisional cutaneous wounds with different diameters in an animal model Determination of osteopontin in monitoring retinal damage in metabolic syndrome 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 Issue Information
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