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：
10380190
负责人：
IAIN HUGH MCKILLOP
金额：
$ 22.5万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380190
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 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/antagonist innovation intrahepatic 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.

概括酒精使用障碍 (AUD) 是美国重大的临床和财务医疗负担在全球范围内，受 AUD 影响的病理学中，肝脏在酒精中发挥着核心作用。新陈代谢使其特别容易受到持续的酒精性肝病（ALD）的损害。大量饮酒，其特点是一系列恶化的肝脏病变（脂肪堆积（肝脂肪变性）、酒精性肝炎、纤维化-肝硬化）在 ALD 中，肝细胞色素 P450 2E1 被诱导代谢乙醇导致肝内乙醛和氧化应激升高，这些因素会增加遗传损伤和肝细胞癌 (HCC) 发展的风险。细胞内脂质运动和储存是维持肝脏和肝脏功能所需的密切调节过程。在健康个体中，全身脂肪酸结合蛋白（FABP）在组织中表达。在健康肝脏中脂质隔离和运动过程中作为关键伴侣的特定方式和功能。 FABP1 是肝细胞中表达的主要 FABP。最近的研究报道了 FABP4（通常是一种异构体）。在脂肪细胞和巨噬细胞中表达）由脂肪细胞合成和释放，充当旁分泌- 特定疾病状态下的内分泌信号分子，包括与脂肪密切相关的癌症我们小组的研究报告 FABP4 mRNA 和蛋白质表达在组织中显着上调。从酒精喂养的啮齿动物中分离出的肝细胞，以及表达 CYP2E1 的 HCC 的酒精代谢 ALD 模型系统中 FABP4 表达增加的这些发现也在组织和细胞中得到了证实。来自 ALD/ALD-HCC 患者的血清在功能上，我们报告外源性 rhFABP4 刺激 ERK-MAPK 和总的来说，这些数据使我们得出结论：JNK 信号传导导致 HCC 体外增殖和迁移。 “ALD 诱导的脂肪变性肝细胞中的酒精代谢导致 FABP4 的诱导合成和释放进而刺激 HCC 细胞生长和迁移”。提出了两个具体目标；目标 1 将确定肝醇的机制。代谢诱导 FABP4 表达，并定义 FABP4 调节的信号传导机制为了实现这一目标，我们将使用从初步数据中获得的知识。采用创新的蛋白质组学方法（细胞信号磷酸化抗体阵列）建立体外模型准确确定 FABP4 调节的信号网络将证明其重要性。 FABP4 信号传导在体内酒精依赖性 HCC 扩张和进展中的作用。肝细胞特异性 FABP4-/- 小鼠 (HS-FABP4-/-) 和肿瘤进展的原位模型同时，我们将扩大对 ALD 和 ALD-HCC 患者组织和血清中 FABP4 的持续分析表达以确定 ALD 和 HCC 进展期间 FABP4 表达改变的临床相关性。