Hepatic protein-tyrosine phosphatase1B and alcoholic liver disease

摘要 酒精性肝病(ALD)是美国肝脏相关死亡的重要原因。 这种疾病包括一系列疾病，从脂肪变性到酒精性肝炎，以及 可能进展为肝硬变和肝细胞癌。而大多数酗酒者 发展为脂肪肝，只有少数人会发展为酒精性肝炎，10%-15%的人会发展为 肝硬变。尽管公共卫生负担沉重，但目前没有FDA批准的 ALD的药物治疗表明迫切需要开发新的治疗方法。蛋白质酪氨酸 磷酸酶1B(PTP1B；由Ptpn1编码)是一种广泛表达的磷酸酶，是一种 已建立代谢调节器。鉴于PTP1B缺乏和 药理抑制它是治疗代谢性疾病的一个有吸引力的靶点。至 研究PTP1B在ALD中的作用我们将使用功能丧失的方法来研究 PTP1B在肝细胞和肝星状细胞中的作用此外，我们还将确定 肝脏PTP1B作用的分子机制及其潜在的预防作用 PTP1B抑制对ALD的治疗价值。初步数据显示，肝脏- 特异性PTP1B阻断减轻乙醇诱导的慢性脂肪变性和炎症 外加ALD狂欢小鼠模型。此外，肝脏PTP1B缺乏可减弱乙醇- 引起氧化应激和炎症。总之，这些发现表明PTP1B 对ALD患者肝功能的影响以及PTP1B的药物抑制可能呈现一种 疾病管理中的治疗方法。

ABSTRACT Alcoholic liver disease (ALD) is a significant cause of liver-related death in the United States. The disease covers a spectrum of disorders ranging from steatosis to alcoholic hepatitis and may progress to cirrhosis and hepatocellular carcinoma. While the majority of heavy drinkers develop fatty liver, only a minority will progress to alcoholic hepatitis, and 10-15% develop cirrhosis. Despite the significant public health burden, there is currently no FDA-approved pharmacotherapy for ALD indicating the urgent need to develop new therapies. Protein tyrosine phosphatase 1B (PTP1B; encoded by Ptpn1) is a widely expressed phosphatase and an established metabolic regulator. Given the beneficial effects of PTP1B deficiency and pharmacological inhibition it is an attractive therapeutic target for metabolic diseases. To investigate the role of PTP1B in ALD we will use a loss-of-function approach to investigate the contribution of PTP1B in hepatocytes and hepatic stellate cells. Also, we will determine the molecular mechanisms underlying hepatic PTP1B action and explore the potential preventative and therapeutic value of PTP1B inhibition in ALD. Preliminary data demonstrated that liver- specific PTP1B disruption attenuated ethanol-induced steatosis and inflammation in the chronic plus binge mouse model of ALD. Moreover, hepatic PTP1B deficiency attenuated ethanol- induced oxidative stress and inflammation. Together, these findings suggest that PTP1B impacts hepatic function in ALD and that PTP1B pharmacological inhibition may present a therapeutic approach in disease management.