Canagliflozin protects against non-alcoholic steatohepatitis in type-2 diabetic rats through zinc alpha-2 glycoprotein up-regulation
Canagliflozin protects against non-alcoholic steatohepatitis in type-2 diabetic rats through zinc alpha-2 glycoprotein up-regulation
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DOI：
10.1016/j.ejphar.2018.03.043
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发表时间：
2018-06-05
影响因子：
5
通讯作者：
Mahmoud, Nevertyty M.
中科院分区：
文献类型：
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作者：
Kabil, Soad L.;Mahmoud, Nevertyty M.
血糖升高和胰岛素抵抗是非酒精性脂肪性肝炎（NASH）的触发因素。我们研究了钠葡萄糖协同转运蛋白2（SGLT 2）抑制剂卡格列净对2型糖尿病大鼠NASH发展的影响以及可能的潜在机制，并首次研究了卡格列净对肝脏锌-α 2-糖蛋白（ZAG）水平的影响。用烟酰胺和链脲佐菌素处理大鼠以降低胰岛素分泌能力，然后喂食高脂饮食8周。在此期间，将糖尿病高脂饮食大鼠分为三组：未给药组、卡格列净10 mg/kg给药组和卡格列净20 mg/kg给药组。卡格列净显著降低了糖尿病高脂饮食大鼠中升高的血糖和糖化血红蛋白（HbA 1c）水平。此外，糖尿病高脂饮食诱导NASH发展，表现为肝脏重量增加、肝脏脂质蓄积和肝脏ZAG表达降低以及血清丙氨酸氨基转移酶升高;所有这些变化在卡格列净给药大鼠中均逆转。此外，卡格列净成功上调正常和糖尿病高脂肪喂养大鼠的肝脏ZAG水平，降低血清和肝脏炎性细胞因子水平以及降低血清半胱天冬酶-3水平和增强肝脏Bcl-2表达。此外，卡格列净可减轻肝脏氧化应激，提高抗氧化酶活性和总抗氧化能力。卡格列净的所有这些作用均具有剂量依赖性。结论：SGLT 2载体-卡格列净-在治疗糖尿病相关NASH中具有有益作用。
Elevated blood glucose and insulin resistance are triggering factors for non-alcoholic steatohepatitis (NASH). We investigated the effects of the Sodium Glucose co-Transporter 2 (SGLT2) inhibitor canagliflozin on NASH development in rats with type 2 diabetes mellitus as well as the possible underlying mechanisms and for the first time the effect of canagliflozin on the hepatic zinc-alpha 2-glycoprotein (ZAG) levels.& para;& para;Rats were treated with nicotinamide and streptozotocin to reduce the insulin secretory capacity then fed high fat diet for 8 weeks. The diabetic high fat diet rats were divided into three groups; untreated group, canagliflozin 10 mg/kg treated group and canagliflozin 20 mg/kg treated group during this period. The elevated blood glucose and glycated haemoglobin (HbA1c) levels in the diabetic high fat diet rats were significantly reduced by canagliflozin. Moreover, the diabetic high fat diet induced NASH development as evidenced by liver weight gain, hepatic lipid accumulation and low hepatic ZAG expression as well as increased serum alanine aminotransferase; all these changes were reversed in rats treated with canagliflozin. Additionally, canagliflozin succeeded to upregulate the hepatic ZAG levels in both normal and diabetic high fat fed rats, lower the serum and hepatic inflammatory cytokines levels as well as lower the serum caspase-3 levels and enhanced hepatic Bcl-2 expression. Also, canagliflozin attenuated hepatic oxidative stress and elevated the antioxidant enzymes activity as well as the total antioxidant capacity. All these effects of canagliflozin were dose dependant. Conclusion: SGLT2 inhibitor-canagliflozin- has beneficial effects in treatment of NASH associated with diabetes mellitus.