Shi Changxuan, Wang Yuanfang, Gao Jing, Chen Si, Zhao Xiangqian, Cai Chengchao, Guo Chang, Qiu Longxin
Department of Biological Science and Technology, School of Life Sciences, Longyan University, Longyan, Fujian 364012, P.R. China.
Mol Med Rep. 2017 Sep;16(3):2767-2772. doi: 10.3892/mmr.2017.6895. Epub 2017 Jun 30.
Aldose reductase (AR) expression is elevated in the livers of patients with alcoholic liver diseases. However, the role of AR in the development of alcoholic liver diseases remains unclear. The aim of the present study was to determine the effect of AR inhibition on ethanol‑induced hepatosteatosis in vivo and in vitro, and to identify possible underlying molecular mechanisms. Alcoholic fatty livers were induced in C57BL/6 mice by feeding the mice with Lieber‑DeCarli liquid diets. The expression of AR protein was elevated in the liver tissue of C57BL/6 mice fed with an ethanol diet and in mouse AML12 liver cells exposed to ethanol. In addition to the elevation in AR, hepatic steatosis was observed in ethanol diet‑fed mice, and this ethanol‑induced steatosis was significantly attenuated by inhibiting AR activity with a specific inhibitor, zopolrestat. The suppressive effect of AR inhibition was associated with decreased levels of hepatic lipoperoxides, decreased protein expression of hepatic cytochrome P450 2E1 (CYP2E1), increased phosphorylation of 5'‑AMP‑activated protein kinase (AMPK) and decreased mRNA expression of tumor necrosis factor‑α (TNF‑α). Treatment with the AR inhibitor attenuated the level of lipid accumulation and oxidative stress, activated AMPK, and suppressed the mRNA expression of TNF‑α, interleukin‑6 and transforming growth factor‑β1 in ethanol‑treated AML12 cells. The results of the present study demonstrated that inhibition of AR ameliorated alcoholic liver disease in vivo and in vitro, in part by activating AMPK, decreasing CYP2E1‑mediated oxidative stress and ameliorating the expression of pro‑inflammatory cytokines.
醛糖还原酶（AR）在酒精性肝病患者肝脏中的表达升高。然而，AR在酒精性肝病发展过程中的作用仍不清楚。本研究的目的是确定AR抑制在体内和体外对乙醇诱导的肝脂肪变性的影响，并确定可能的潜在分子机制。通过给C57BL/6小鼠喂食Lieber-DeCarli液体饮食诱导酒精性脂肪肝。在喂食乙醇饮食的C57BL/6小鼠的肝脏组织以及暴露于乙醇的小鼠AML12肝细胞中，AR蛋白的表达升高。除了AR升高外，在喂食乙醇饮食的小鼠中观察到肝脂肪变性，并且通过用特异性抑制剂唑泊司他抑制AR活性，这种乙醇诱导的脂肪变性显著减轻。AR抑制的抑制作用与肝脂质过氧化物水平降低、肝细胞色素P450 2E1（CYP2E1）蛋白表达降低、5'-AMP激活蛋白激酶（AMPK）磷酸化增加以及肿瘤坏死因子-α（TNF-α）mRNA表达降低有关。用AR抑制剂处理可减轻乙醇处理的AML12细胞中的脂质积累和氧化应激水平，激活AMPK，并抑制TNF-α、白细胞介素-6和转化生长因子-β1的mRNA表达。本研究结果表明，抑制AR可在体内和体外改善酒精性肝病，部分原因是通过激活AMPK、降低CYP2E1介导的氧化应激以及改善促炎细胞因子的表达。
