Nicotine and alcoholic liver disease

尼古丁和酒精性肝病

• 批准号: 10086128
• 负责人: Yongke Lu
• 金额: $ 34.24万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10086128
• 关键词: Nicotine; alcoholic; liver; disease

ABSTRACT Alcohol abuse is a significant global health problem. Chronic alcohol drinking can induce alcoholic liver disease, which ranges from steatosis (fatty liver) to steatohepatitis, fibrosis and cirrhosis. About 90% of heavy alcohol drinkers develop alcoholic fatty livers (AFL), an onset of alcoholic liver disease. Recently, we found that CYP2A5 (CYP2A6 in humans) is induced by chronic ethanol feeding and CYP2A6 is elevated in alcoholic patients. CYP2A5/6 is a major nicotine metabolic enzyme. Alcohol and tobacco are frequently co-abused and tobacco smoke can increase AFL. We found that nicotine, a major addictive forming alkaline in tobacco smoke, can enhance AFL and hypertriglyceridemia (HTG), which was observed in WT mice but not in cyp2a5-/- mice. PPARα-regulated FGF21 is a novel metabolic regulator highly expressed in liver. We observed a constitutive elevation of hepatic PPARα-FGF21 in cyp2a5-/- mice. Ethanol-induced HTG observed in pparα-/- mice with an extremely low serum FGF21 can be blocked by the treatment of rFGF21. Ethanol/nicotine-induced AFL was more pronounced in liver-specific FGF21 KO mice. These results suggest that FGF21 may play an important role in FGF21 modulates cellular activity through FGF receptor 1 (FR1), which is mainly expressed in adipose tissues and to a much lesser extent in liver. We didn’t observe any difference in AFL and HTG between liver- specific FR1 KO mice and their WT control mice, suggesting that in our model the more important might be adipose FR1 but not liver FR1. Liver FGF21 can be released into blood to act in an endocrine manner. FGF21 can stimulate adipocytes to secret adiponectin, which in turn acts on the liver to ameliorate AFL. In AIM 1, we will reintroduce CYP2A5 back to cyp2a5-/- mice via AAV8 to validate the essential role of CYP2A5 in the nicotine-enhanced AFL and HTG and apply cotinine and antioxidant to examine the role of CYP2A5-produced nicotine metabolites and oxidative stress in the nicotine-enhanced AFL and HTG. In AIM 2, we will examine the role of a PPARα-FGF21 axis in the nicotine-enhanced AFL and HTG by applying pparα-/-/cyp2a5-/- mice, liver- specific FGF21 knockout mice and PPARα specific agonist WY-14,643. In AIM 3, cell-cell interaction in cell co- culture system of adipocytes and hepatocytes will be examined to reflect organ-organ interaction between adipose tissue and liver. Adiponectin knockout mice will be treated with rFGF21 to evaluate if liver FGF21 exerts its action in adipose tissue through adiponectin i.e. the PPARα-FGF21-adiponectin to regulate nicotine- enhanced AFL and HTG. At last, adiponectin and CYP2A5 double knockout mice will be applied to investigate the role of adiponectin in the observation that nicotine-enhanced AFL and HTG was observed in WT mice but not in cyp2a5-/- mice.

抽象的 酗酒是一个重大的全球健康问题。慢性饮酒会诱导酒精性肝病， 范围从脂肪变性（脂肪肝）到脂肪性肝炎，纤维化和肝硬化。大约90％的重酒精 饮酒者会出现酒精脂肪肝（AFL），这是酒精性肝病的发作。最近，我们发现 CYP2A5（人类中的CYP2A6）是由慢性乙醇喂养诱导的，并且在酒精中升高CYP2A6 患者。 CYP2A5/6是主要的尼古丁代谢酶。酒精和烟草经常被共施用， 烟草烟雾可以增加AFL。我们发现，尼古丁是一种主要的添加剂，在烟草烟雾中形成饮酒， 可以增强在WT小鼠中观察到的AFL和高甘油三酯血症（HTG），但在CYP2A5 - / - 小鼠中观察到。 PPARα调节的FGF21是一种在肝脏中高度表达的新型代谢调节剂。我们观察到了一个构成 CYP2A5 - / - 小鼠中肝PPARα-FGF21的升高。乙醇诱导的HTG在PPARα - / - 小鼠中观察到 极低的血清FGF21可以通过RFGF21的处理来阻止。乙醇/尼古丁诱导的AFL是 在肝特异性FGF21 KO小鼠中更为明显。这些结果表明FGF21可能起重要 在FGF21中的作用通过FGF受体1（FR1）调节细胞活性，该活性主要在脂肪中表达 组织，肝脏的程度较小。我们没有观察到肝之间的AFL和HTG有任何差异 - 特定的FR1 KO小鼠及其WT对照小鼠，这表明在我们的模型中可能更重要 脂肪FR1但不是肝脏FR1。肝FGF21可以被释放到血液中，以内分泌方式作用。 FGF21 可以刺激脂肪细胞对秘密脂联素的脂肪细胞，而脂肪细胞反过来作用于肝脏以改善AFL。在AIM 1中，我们 将通过AAV8重新引入CYP2A5回到CYP2A5 - / - 小鼠，以验证CYP2A5在 尼古丁增强的AFL和HTG，并施用可替宁和抗氧化剂来检查CYP2A5产生的作用 尼古丁代谢物和尼古丁增强的AFL和HTG中的氧化应激。在AIM 2中，我们将检查 PPARα-FGF21轴在尼古丁增强AFL和HTG中的作用，通过施加PPARα-/ - / - /CYP2A5 - / - 小鼠，肝脏 - 特定的FGF21敲除小鼠和PPARα特异性激动剂WY-14,643。在AIM 3中，细胞中的细胞 - 细胞相互作用 将检查脂肪细胞和肝细胞的培养系统，以反映有机器官的相互作用 脂肪组织和肝脏。脂联素基因敲除小鼠将用RFGF21治疗，以评估肝FGF21是否 通过脂联素在脂肪组织中发挥作用 增强的AFL和HTG。最后，将应用脂联素和CYP2A5双基因敲除小鼠调查 脂联素在WT小鼠中观察到的尼古丁增强AFL和HTG的作用 不在CYP2A5 - / - 小鼠中。