FABP4 Released from Steatotic Hepatocytes in Alcoholic Liver Disease Enhances Hepatic Tumor Progression

酒精性肝病中脂肪肝细胞释放的 FABP4 促进肝肿瘤进展

基本信息

批准号：
10491369
负责人：
IAIN HUGH MCKILLOP
金额：
$ 18.58万
依托单位：
CAROLINAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491369
关键词：
Acetaldehyde Adipocytes Adipose tissue Affect Alcohol consumption Alcohol dehydrogenase Alcohol dependence Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Animals Antibodies Binding Biological Models CYP2E1 gene Cell Fractionation Cell Proliferation Cell physiology Cells Cellular Metabolic Process Cellular biology Chronic Cirrhosis Clinical Consumption Cytochromes Data Data Reporting Deacetylation Development Diagnostic Neoplasm Staging Diethylnitrosamine Disease Disease Progression Disease model Endocrine Endothelial Cells Environment Ethanol Ethanol Metabolism Event Excision FABP1 gene FABP4 gene Fatty Liver Fatty acid glycerol esters Fibrosis Future Genetic Risk Genetic Transcription Healthcare Hepatic Hepatic Tissue Hepatocyte Hepatology Homeostasis Human In Vitro Individual Informed Consent Institutional Review Boards Knowledge Label Letters Lipids Liver Liver diseases Liver neoplasms MAP Kinase Gene MAPK8 gene Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Mediating Membrane Metabolism Modeling Molecular Molecular Biology Molecular Chaperones Molecular and Cellular Biology Movement Mus Neoplasm Metastasis Nonesterified Fatty Acids Nuclear Operative Surgical Procedures Outcome Oxidative Stress Pathologic Pathology Pathway interactions Patients Pharmacology Primary carcinoma of the liver cells Process Protein Isoforms Proteins Proteomics Protocols documentation Recurrence Regulation Reporting Rodent Rodent Model Role SIRT1 gene Sampling Series Serum Severities Signal Pathway Signal Transduction Signaling Molecule System Tissues Transportation Tumor Expansion United States Western Blotting alcohol use disorder base cell growth cell motility clinically relevant exposed human population fatty acid-binding proteins feeding fomepizole hepatoma cell in vitro Model in vivo inhibitor innovation intrahepatic liver cancer model mRNA Expression macrophage microvesicles migration mouse model neoplastic cell novel paracrine protein expression receptor response therapy design transcription factor tumor tumor progression

项目摘要

SUMMARY Alcohol use disorders (AUDs) are significant clinical and financial healthcare burdens in the United States and globally. Within the spectrum of pathologies affected by AUDs, the central role of the liver in alcohol metabolism makes it particularly susceptible to damage. Alcoholic liver disease (ALD) arises from sustained, heavy alcohol ingestion and is characterized by a series of worsening liver pathologies (fat accumulation (hepatosteatosis), alcoholic hepatitis, fibrosis-cirrhosis). In ALD, hepatic cytochrome P450 2E1 is induced to metabolize ethanol leading to elevated intrahepatic acetaldehyde and oxidative stress, factors that increase the risk of genetic damage and development of hepatocellular carcinoma (HCC). Intracellular lipid movement and storage are closely regulated processes required to maintain liver and systemic homeostasis. In healthy individuals fatty acid binding proteins (FABPs) are expressed in a tissue- specific manner and function as critical chaperones during lipid sequestration and movement. In the healthy liver, FABP1 is the predominant FABP expressed in hepatocytes. Recent studies report FABP4 (an isoform usually expressed in adipocytes and macrophages) is synthesized and released by adipocytes to act as a paracrine- endocrine signaling molecule in specific disease states, including cancers arising in close proximity to adipose tissue. Studies by our group report FABP4 mRNA and protein expression is dramatically upregulated in hepatocytes isolated from alcohol-fed rodents, and following alcohol metabolism by CYP2E1-expressing HCC cells. These findings of increased FABP4 expression in ALD model systems are also evidenced in tissue and serum from ALD/ALD-HCC patients. Functionally, we report exogenous rhFABP4 stimulates ERK-MAPK and JNK signaling leading to HCC proliferation and migration in vitro. Collectively, these data have led us to hypothesize that “alcohol metabolism in ALD-induced steatotic hepatocytes leads to the induction of FABP4 synthesis and release which in turn stimulates HCC cell growth and migration”. Two Specific Aims are proposed; Aim 1 will determine the mechanism[s] by which hepatic alcohol metabolism induces FABP4 expression, and define the signaling mechanism[s] by which FABP4 regulates hepatoma cellfunction. To achieve this, we will combine knowledge derived from our Preliminary Data using established in vitro models with innovative proteomic approaches (Cell Signaling Phospho-Antibody Array) to accurately determine the signaling networks regulated by FABP4. Aim 2 will demonstrate the significance of FABP4 signaling in alcohol-dependent HCC expansion and progression in vivo. These studies will utilize a novel hepatocyte-specific FABP4-/- mouse (HS-FABP4-/-) and an orthotopic model of tumor progression. In parallel, we will expand our ongoing analyses of tissue and serum from ALD and ALD-HCC patients for FABP4 expression to determine the clinical relevance of altered FABP4 expression during ALD and HCC progression.

概括在美国，酒精使用障碍（AUDS）是重要的临床和财务保健伯恩斯和全球。在受aud的病理范围内，肝脏在酒精中的核心作用代谢使其特别容易受到损害。酒精性肝病（ALD）来自持续性，大量酒精摄入，其特征是一系列令人担忧的肝病（脂肪积累）（肝脏肝脏病），酒精性肝炎，纤维化 - 卷发）。在ALD中，肝细胞色素P450 2E1被诱导为代谢乙醇导致肝内乙醛升高和氧化应激，增加了增加的因素遗传损害的风险和肝细胞癌（HCC）的发展。细胞内脂质运动和储存是维持肝脏所需的密切调节过程系统性稳态。在健康个体中，脂肪酸结合蛋白（FABP）在组织中表达在脂质隔离和运动过程中，特定的方式和功能是关键伴侣。在健康的肝脏中， FABP1是在肝细胞中表达的主要FABP。最近的研究报告Fabp4（通常在脂肪细胞和巨噬细胞中表达）是由脂肪细胞合成并释放的，可作为旁氨酸特定疾病状态中的内分泌信号分子，包括与脂肪紧密相近的癌症组织。我们的小组报告Fabp4 mRNA和蛋白质表达的研究大大更新从酒精喂养的啮齿动物中分离出来的肝细胞，并通过表达CYP2E1的HCC来代谢。细胞。在组织和来自ALD/ALD-HCC患者的血清。在功能上，我们报告了外源性Rhfabp4刺激ERK-MAPK，并且 JNK信号传导导致HCC增殖和体外迁移。总的来说，这些数据使我们进入假设“ ALD诱导的脂肪性肝细胞中的酒精代谢会导致Fabp4的引入合成和释放反过来刺激HCC细胞的生长和迁移。提出了两个具体的目标； AIM 1将确定肝醇的机制代谢诱导FABP4表达，并定义了FABP4调节的信号传导机制肝癌细胞功能。为了实现这一目标，我们将结合使用初步数据得出的知识建立了具有创新蛋白质组学方法（细胞信号磷酸抗体阵列）的体外模型 AIM 2将证明准确确定由FABP4调节的信号网络的重要性。依赖酒精依赖性HCC膨胀和体内进展的FABP4信号传导。这些研究将利用小说肝细胞特异性FABP4 - / - 小鼠（HS-FABP4 - / - ）和肿瘤进展的原位模型。并联，我们将扩大对Fabp4的ALD和ALD-HCC患者的组织和血清的持续分析表达以确定ALD和HCC进展过程中FABP4表达改变的临床相关性。