Lipotoxicity and Liver Inflammation

脂毒性和肝脏炎症

• 批准号: 10533359
• 负责人: Samar Ibrahim
• 金额: $ 35.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533359
• 关键词: Adhesions; Adoptive Transfer; Affinity; Anti-Inflammatory Agents; Attenuated; Binding; Biochemical; Biogenesis; Biological; Biology; Cell Adhesion Inhibition; Cell Adhesion Molecules; Cell Communication; Cell model; Cell surface; Cells; Childhood; Choline; Cytoskeleton; Data; Development; Diet; Disease; Encapsulated; Endothelial Cells; Endothelium; Exposure to; Flow Cytometry; Functional disorder; GTPase-Activating Proteins; Goals; Hepatic; Hepatocyte; Home; Human; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrin Inhibition; Integrins; Isotope Labeling; Leukocytes; Ligands; Link; Lipids; Liver; Liver diseases; Macrophage; Mediating; Mediator; Modeling; Molecular; Molecular Conformation; Molecular Profiling; Mus; NF-kappa B; Nanoscale Fluidic Technology; Nonesterified Fatty Acids; Obesity; Pathogenesis; Pathway interactions; Positron-Emission Tomography; Proteome; Public Health; Publishing; Research; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Sterility; Stress; Surface; Testing; Therapeutic Intervention; Vascular Cell Adhesion Molecule-1; Visualization; experimental study; extracellular vesicles; hepatocyte injury; inhibitor; innovation; insight; liver inflammation; liver injury; member; microfluidic technology; monocyte; mouse model; nanomedicine; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; pharmacologic; prevent; recruit; therapeutic target; trafficking; vesicular release

PROJECT SUMMARY Overall Objectives of this proposal are to define mechanisms linking hepatocyte injury during lipotoxicity with hepatic inflammation in nonalcoholic steatohepatitis (NASH). NASH is the most common pediatric liver disease characterized by abundant circulating saturated free fatty acids (SFAs), along with hepatocyte lipotoxicity and monocyte-derived macrophage mediated liver inflammation. Hepatocyte lipotoxicity and liver injury are, in part, induced by SFAs and their intracellular metabolite lysophosphatidyl choline (LPC). However, cellular and molecular mechanisms linking hepatocyte lipotoxicity to liver inflammation are not completely understood. Emerging data implicate extracellular vesicles (EVs) released during hepatocyte lipotoxic stress in liver inflammation. In published and preliminary experiments, we have discovered that, lipotoxic hepatocytes release a large number of proinflammatory EVs; these EVs are enriched with the adhesion molecule integrin β1 (ITGβ1) and promote monocytes adhesion to liver sinusoidal endothelial cells (LSECs) in vitro. We also demonstrated that the expression of ITGβ1 ligand, vascular cell adhesion molecule (VCAM) 1, on LSECs is increased during lipotoxicity. Based on these novel observations, we have formulated the CENTRAL HYPOTHESIS that lipotoxic hepatocytes release ITGβ1-enriched EVs that recruit and retain monocyte in the liver promoting inflammation. We will employ current biochemical and cell biological approaches that include microfluidic technology, Nanoscale flow cytometry, and 89Zirconium isotopically labelled EVs visualized with positron emission tomography (PET) scan to test this hypothesis. Our independent SPECIFIC AIMS will test three integrated hypotheses. First, we will demonstrate that hepatocyte lipotoxicity induces an active conformation switch of ITGβ1, enhancing its endocytic trafficking and release into EVs. Second, we will define the mechanism of increased VCAM1 expression during lipotoxicity. We will also directly test the hypothesis that lipotoxic hepatocyte-derived EVs mediate monocytes adhesion to LSECs, through ITGβ1-VCAM1 binding interaction, in vitro by using microfluidic technology. Third, using a mouse model of NASH, we will test the hypothesis that pharmacological inhibition of integrin β1 or conditional deletion of endothelial VCAM1 is protective against liver inflammation. We will also demonstrate that adoptively-transferred lipotoxic hepatocyte- derived EVs home to the LSECs of recipient mice through their high affinity integrin β1cargo. We have established the requisite cell and mouse models to study lipotoxicity, integrin signaling and EV biology. This proposal is technically and conceptually innovative, as it seeks to integrate the molecular mechanisms underlying hepatocyte injury, integrin activation and trafficking with liver inflammation, and links hepatic pathophysiology with nanomedicine. This research has the potential to identify new therapeutic strategies, namely integrin and VCAM1 inhibitors, to prevent or reverse liver injury and inflammation in human NASH.

项目总结