Hamarneh Sulaiman R, Kim Byeong-Moo, Kaliannan Kanakaraju, Morrison Sara A, Tantillo Tyler J, Tao Qingsong, Mohamed Mussa M Rafat, Ramirez Juan M, Karas Aaron, Liu Wei, Hu Dong, Teshager Abeba, Gul Sarah Shireen, Economopoulos Konstantinos P, Bhan Atul K, Malo Madhu S, Choi Michael Y, Hodin Richard A
Department of Surgery, Harvard Medical School, Massachusetts General Hospital, 15 Parkman Street, Boston, MA, 02114, USA.
Gastrointestinal Unit, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
Dig Dis Sci. 2017 Aug;62(8):2021-2034. doi: 10.1007/s10620-017-4576-0. Epub 2017 Apr 19.
Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease.
Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease.
Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes.
IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.
肠道细菌衍生的因子在肝脏炎症途径激活及酒精性肝病发病机制中起主要作用。肠道刷状缘酶肠碱性磷酸酶（IAP）可使多种细菌促炎因子解毒，还具有维持肠道屏障功能的作用。本研究旨在探讨口服补充IAP是否能预防酒精性肝病。
小鼠接受急性暴饮或慢性乙醇暴露以诱导酒精性肝损伤和脂肪变性，并补充或不补充IAP。评估肝组织的生化、炎症和组织病理学变化。采用体外共培养系统研究酒精和IAP处理对肝星状细胞激活及其在酒精性肝病发生发展中作用的影响。
在急性暴饮模型中，与单纯乙醇组相比，IAP预处理导致血清丙氨酸转氨酶显著降低。IAP治疗减轻了酒精性脂肪肝的发展，降低了肝脏促炎细胞因子和血清LPS水平，并预防了酒精性肠道屏障功能障碍。最后，IAP改善了肝星状细胞的激活，并阻止了它们对肝细胞的脂肪生成作用。
IAP治疗可保护小鼠免受酒精性肝毒性和脂肪变性。口服补充IAP可能是预防人类酒精性肝病的一种新疗法。
