Zhu ZhanTao, Jiang ZhiAn, Zhou JunYing, Zhou DongFang, Wang Wei, Zhao CaiYan, Zhen Zhen, Nanji Amin A
Department of Infectious disease , Third Hospital, Hebei Medical University, Shijiazhuang, China.
Alcohol Clin Exp Res. 2014 Jun;38(6):1510-9. doi: 10.1111/acer.12418. Epub 2014 May 5.
Alcoholic liver disease (ALD) continues to be a major cause of morbidity worldwide. The exact mechanisms for ALD pathogenesis are not fully understood. There is currently no known available drug for ALD. Previous studies have suggested that ethanol (EtOH)-induced hepatic insulin resistance, through the inhibition of adenosine monophosphate-activated protein kinase (AMPK) and the expression of adiponectin as well as downstream enzymes, contribute to the development of ALD. This study was to determine the effects of EtOH on AMPK activity as well as the protective effect of metformin.
Forty male Wistar rats weighing 200 ± 20 g were randomized into 4 groups (n = 10) as follows: A = control group-rats received rodent chow; B = control + metformin group-rats received metformin (200 mg/kg/d intragastrically [IG]) at 21:00; C = EtOH group-rats were gavaged with alcohol of gradually increasing concentrations (30 to 60%, 5 to 9 g/kg/d) twice a day (9:00 and 16:00); D = EtOH + metformin group-rats received the same amount of EtOH as the rats in group C, and in addition received metformin (200 mg/kg/d IG) at 21:00. After 16 weeks, blood and liver samples were collected for further study.
Chronic EtOH consumption led to liver injury both histologically and biochemically accompanied by insulin resistance, reduced AMPK activity, and dysregulation of downstream enzymes. Decreased levels of circulating adiponectin and decreased expression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) and peroxisome proliferator-activated receptors-α (PPAR-α) in the hepatic tissue were observed. Treatment with metformin attenuated the severity of liver injury, restored AMPK activity and normalized the expression of acetyl-CoA carboxylase and fatty acid synthase. In addition, metformin also increased the circulating adiponectin and liver adiponectin receptor 2 expression. Furthermore, PGC-1α and PPAR-α activities were also restored.
EtOH exposure induces hepatic insulin resistance. Metformin improved insulin resistance and reversed liver injury through the activation of AMPK and normalized adiponectin signaling making metformin a promising drug for the treatment of ALD.
酒精性肝病（ALD）仍是全球发病的主要原因。ALD发病的确切机制尚未完全明确。目前尚无已知的可用于治疗ALD的药物。既往研究表明，乙醇（EtOH）通过抑制腺苷单磷酸激活蛋白激酶（AMPK）、脂联素及其下游酶的表达诱导肝脏胰岛素抵抗，进而促使ALD的发生发展。本研究旨在确定EtOH对AMPK活性的影响以及二甲双胍的保护作用。
将40只体重200±20 g的雄性Wistar大鼠随机分为4组（n = 10），分组如下：A组为对照组，大鼠给予啮齿类动物饲料；B组为对照组+二甲双胍组，大鼠于21:00接受二甲双胍（200 mg/kg/d，灌胃[IG]）；C组为EtOH组，大鼠每天两次（9:00和16:00）给予浓度逐渐增加的酒精（30%至60%，5至9 g/kg/d）灌胃；D组为EtOH+二甲双胍组，大鼠接受与C组相同剂量的EtOH，此外于21:00接受二甲双胍（200 mg/kg/d，灌胃）。16周后，采集血液和肝脏样本用于进一步研究。
长期摄入EtOH导致肝脏组织学和生化损伤，伴有胰岛素抵抗、AMPK活性降低以及下游酶的失调。观察到循环脂联素水平降低，肝组织中增殖激活受体γ辅激活因子-1α（PGC-1α）和过氧化物酶体增殖物激活受体-α（PPAR-α）表达减少。二甲双胍治疗减轻了肝损伤的严重程度，恢复了AMPK活性，并使乙酰辅酶A羧化酶和脂肪酸合酶的表达正常化。此外，二甲双胍还增加了循环脂联素和肝脏脂联素受体2的表达。此外，PGC-1α和PPAR-α的活性也得到恢复。
EtOH暴露诱导肝脏胰岛素抵抗。二甲双胍通过激活AMPK改善胰岛素抵抗并逆转肝损伤，使脂联素信号正常化，这使得二甲双胍成为治疗ALD的一种有前景的药物。
