Nicotine and Alcoholic Liver Disease

尼古丁和酒精性肝病

• 批准号: 9361692
• 负责人: Yongke Lu
• 金额: $ 35.44万
• 依托单位: EAST TENNESSEE STATE 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/9361692
• 关键词: Adenoviruses; Adipocytes; Adipose tissue; Agonist; Alcohol abuse; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Antioxidants; Ascorbic Acid; Back; Blood; CYP2A5 gene; CYP2E1 gene; Chronic; Cirrhosis; Cotinine; Cysteine; Development; Endocrine; Enzymes; Ethanol; Ethanol toxicity; Fatty Liver; Fibroblast Growth Factor Receptors; Fibrosis; Health; Human; Hypertriglyceridemia; Knock-out; Knockout Mice; Lead; Liver; Liver Cirrhosis; Liver Dysfunction; Liver Fibrosis; Mediating; Metabolic; Metabolism; Modeling; Mus; Nicotine; Oxidative Stress; PPAR alpha; Pathway interactions; Patients; Play; Role; Sampling; Satellite Viruses; Serum; Steatohepatitis; Testing; Therapeutic Intervention; Tobacco; Tobacco smoke; Up-Regulation; adiponectin; autocrine; chronic alcohol ingestion; design; feeding; fibroblast growth factor 21; global health; hydroxycotinine; nicotine abuse; novel; prevent; problem drinker; reconstitution

 DESCRIPTION (provided by applicant): 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 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 alcoholic fatty liver. Our preliminary results indicate that nicotine can enhance AFL and hypertriglyceridemia (HTG), which was observed in WT mice but not in cyp2a5-/- mice. In AIM 1 we will reintroduce CYP2A5 back to cyp2a5-/- mice via AAV8 to confirm the essential role of CYP2A5 in the nicotine-enhanced AFL and HTG and apply cotinine and antioxidants to examine the role of CYP2A5-produced nicotine metabolites and oxidative stress in the nicotine-enhanced AFL and HTG. FGF21 is a novel metabolic regulator highly expressed in liver. Liver FGF21 is regulated by PPARα. Constitutive elevation of PPARα-FGF21 in liver was observed in cyp2a5-/- mice. Ethanol-induced HTG, which was observed in pparα-/- mice but not in WT mice, can be blocked by rFGF21. FGF21 modulates cellular activity through FGF receptor 1 (FR1), which is mainly expressed in adipose tissues. 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 2 we will examine the role of a PPARα-FGF21 axis in the nicotine- enhanced AFL and HTG by applying PPARα and FGF21, liver-specific FGF21 knockout mice and PPARα specific agonist WY-14,643. In AIM 3 adipose-specific FR1 knockout mice and adiponectin knockout mice will be applied to evaluate if PPARα-regulated 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.

 描述（适用提供）：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，从脂肪变性（脂肪肝）到脂肪hemiapatis，纤维化和肝硬化。大约90％的重酒精饮用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是由慢性乙醇喂养诱导的，并且酒精患者的CYP2A6升高。 CYP2A5/6是主要的尼古丁代谢酶。酒精和烟草经常共施用，烟草烟雾可以增加酒精脂肪肝。我们的初步结果表明，尼古丁可以增强AFL和高甘油三酯血症（HTG），这在WT小鼠中观察到，但在CYP2A5 - / - 小鼠中观察到。 In AIM 1 we will reintroduce CYP2A5 back to cyp2a5-/- mice via AAV8 to confirm the essential role of CYP2A5 in the nicotine-enhanced AFL and HTG and apply cotinine and antioxidants to examine the role of CYP2A5-produced nicotine metabolites and oxidative stress in the nicotine-enhanced AFL and HTG. FGF21是一种在肝脏中高度表达的新型代谢调节剂。肝FGF21受PPARα调节。在CYP2A5 - / - 小鼠中观察到肝脏中PPARα-FGF21的组成率升高。乙醇诱导的HTG在PPARα - / - 小鼠中观察到，但在WT小鼠中观察到，RFGF21可以阻止。 FGF21通过FGF受体1（FR1）调节细胞活性，该活性主要在脂肪组织中表达。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，而脂肪细胞反过来又作用于肝脏以改善AFL。在AIM 2中，我们将通过应用PPARα和FGF21，肝脏特异性FGF21敲除小鼠以及PPARα特异性激动剂WY-14,643来检查PPARα-FGF21轴在尼古丁增强的AFL和HTG中的作用。在AIM 3中，将应用脂肪特异性的FR1基因敲除小鼠和脂联蛋白基因敲除小鼠，以评估PPARα调节的肝FGF21是否通过脂联素（即PPARα-FGF21-粘结剂）在脂肪组织中执行其作用。最后，脂联素和CYP2A5双基因敲除小鼠将用于研究脂联素在WT小鼠中观察到的尼古丁增强的AFL和HTG在观察中的作用，但在CYP2A5 - / - 小鼠中未观察到。