Hepatic protein-tyrosine phosphatase1B and alcoholic liver disease

肝蛋白酪氨酸磷酸酶1B与酒精性肝病

• 批准号: 10020753
• 负责人: Ming-Fo Hsu
• 金额: $ 18.64万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020753
• 关键词: Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Antisense Oligonucleotides; Attenuated; Autophagocytosis; Bioavailable; Biochemical; Body Weight; Cell Death; Cells; Cessation of life; Chronic; Cirrhosis; Clinical; Complex; Data; Development; Disease; Disease Management; Enzymes; Ethanol; FDA approved; Fatty Liver; Genetic; Hepatic; Hepatic Stellate Cell; Hepatic Tissue; Hepatocyte; Homeostasis; Human; Inflammation; Injury; Liver; Malignant Neoplasms; Metabolic; Metabolic Diseases; Minority; Modeling; Molecular; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Overweight; Oxidative Stress; PTPN1 gene; Patients; Pharmacology; Pharmacotherapy; Phosphoric Monoester Hydrolases; Primary carcinoma of the liver cells; Protein Dephosphorylation; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Public Health; Role; Sampling; Signal Transduction; Testing; Therapeutic; Tyrosine; Tyrosine Phosphorylation; United States; Up-Regulation; alcohol effect; effective therapy; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; interdisciplinary approach; liver injury; loss of function; mouse model; novel therapeutics; protein expression; protein tyrosine phosphatase 1B; therapeutic target

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.

摘要 酒精性肝病（ALD）是美国肝脏相关死亡的重要原因。 这种疾病涵盖了从脂肪变性到酒精性肝炎和 可能进展为肝硬化和肝细胞癌。虽然大多数酗酒者 发展脂肪肝，只有少数人会发展为酒精性肝炎，10-15%会发展为酒精性肝炎。 肝硬化尽管公共卫生负担沉重，但目前还没有FDA批准的 药物治疗ALD表明迫切需要开发新的治疗方法。蛋白酪氨酸 磷酸酶1B（PTP 1B;由Ptpn 1编码）是一种广泛表达的磷酸酶， 建立代谢调节器。考虑到PTP 1B缺乏的有益效果， 药理学抑制它是代谢疾病的有吸引力的治疗靶点。到 为了研究PTP 1B在ALD中的作用，我们将使用功能丧失的方法来研究PTP 1B在ALD中的作用。 PTP 1B在肝细胞和肝星状细胞中的作用。此外，我们将确定 肝PTP 1B作用的分子机制，并探索潜在的预防 以及PTP 1B抑制在ALD中的治疗价值。初步数据显示肝脏- 特异性PTP 1B破坏减弱慢性胰腺炎中乙醇诱导的脂肪变性和炎症 再加上酒精性肝病的暴食小鼠模型。此外，肝脏PTP 1B缺乏会减弱乙醇- 引起氧化应激和炎症。总之，这些发现表明PTP 1B 影响ALD患者的肝功能，PTP 1B药理学抑制可能会导致 疾病管理的治疗方法。