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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.

总结