Hepatic Lipotoxicity, Metabolic Homeostasis and NAFLD Pathogenesis

肝脏脂毒性、代谢稳态和 NAFLD 发病机制

基本信息

批准号：
10886869
负责人：
ANNA MAE ELIZABETH DIEHL
金额：
$ 49.31万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10886869
关键词：
Adult Age Aging Biological Aging Blood Cancer Etiology Cell Cycle Arrest Cell Nucleus Cells Cholesterol Chronic Cirrhosis DNA Damage Data Economic Burden Embryo Erinaceidae FRAP1 gene Fatty Acids Fatty Liver Fibrosis Funding Future Harvest Hepatic Hepatocyte Homeostasis Human Incidence Individual Inflammation Inflammatory Injury Insulin Resistance Iron Knowledge Ligands Link Lipid Peroxidation Lipids Liver Liver diseases LoxP-flanked allele Luciferases Malignant neoplasm of liver Membrane Lipids Metabolic Metabolic stress Metabolic syndrome Metabolism Modeling Mus Outcome Pathogenesis Pathway interactions Patients Phenocopy Phenotype Population Predisposition Premature aging syndrome Prevalence Production Public Health Randomized Regenerative capacity Repression Research Severities Signal Pathway Steatohepatitis Stress Stromal Cells Testing Tissues coping disease diagnosis effective intervention flexibility hepatocyte injury improved injured insulin signaling liver development liver injury mitochondrial dysfunction non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel oxidant stress oxidative DNA damage prevent repaired response senescence single nucleus RNA-sequencing single-cell RNA sequencing smoothened signaling pathway stressor success tissue degeneration vector wound healing

项目摘要

Modified Project Summary/Abstract Section Nonalcoholic fatty liver disease (NAFLD) afflicts one in three adults and poses a major public health threat and economic burden because it can cause cirrhosis and liver cancer. These poor outcomes mainly occur in patients with fatty livers who develop hepatocyte injury (lipotoxicity) and nonalcoholic steatohepatitis (NASH) but then mount maladaptive repair responses. Preventing and treating NAFLD-related cirrhosis and liver cancer has been limited by gaps in knowledge about mechanisms that control susceptibility to NASH, and that determine whether responses to repair NASH are effective or maladaptive. This project evaluates the general hypothesis that hepatocyte Hedgehog activity controls susceptibility to NASH (lipotoxicity) and NASH cirrhosis (maladaptive repair). Hedgehog is a morphogenic signaling pathway that orchestrates liver development in embryos. It was thought to be silenced in adult hepatocytes but emerging evidence suggests that it remains active in subpopulations of hepatocytes in adult livers. Because Smoothened (a critical component of the Hedgehog pathway) is directly regulated by lipids, we postulated that the Hedgehog pathway might be dysregulated in NAFLD. We selectively manipulated Smoothened in hepatocytes and applied state-of-the-art approaches, including single cell RNA seq analysis, to determine if/how Hedgehog signaling regulates hepatocyte metabolism. Remarkably, we found that inhibiting Hedgehog activity in hepatocytes was sufficient to induce NAFL and evoke many abnormalities that have been implicated in the pathogenesis of NASH. The current project evaluates a novel conceptual model for NAFLD pathogenesis that derives from our provocative new data showing that hepatocytes require Hedgehog pathway activity to protect themselves from lipotoxic stress caused by iron-catalyzed lipid peroxidation and evidence that loss of Hedgehog signaling in hepatocytes triggers compensatory responses, including over-production of Hedgehog ligands, that drive maladaptive repair responses in Hedgehog-responsive stromal cells. Successful completion of our Aims will broaden current paradigms about NAFLD pathogenesis and open new opportunities for future discovery to improve NAFLD diagnosis and treatment.

修改的项目摘要/摘要部分非酒精性脂肪肝病（NAFLD）折磨了三分之一的成年人，并构成了主要的公共卫生威胁和经济负担，因为它可能导致肝硬化和肝癌。这些较差的结果主要发生在患有肝细胞损伤（脂蛋白毒性）和非酒精性脂肪性肝炎（NASH）但不良适应性修复反应的患者中。防止和治疗与NAFLD相关的肝硬化和肝癌受到了有关控制NASH敏感性的机制的差距，并确定对修复NASH的反应是有效还是适应不良。该项目评估了一个普遍的假设，即肝细胞刺猬活性控制着对NASH的易感性（脂毒性）和NASH肝硬化（不良适应性修复）。刺猬是一种形态发生的信号通路，可在胚胎中精心策划肝发育。人们认为它在成年肝细胞中是沉默的，但新兴的证据表明，它仍然活跃于成年肝脏的肝细胞亚群中。由于平滑（刺猬途径的关键成分）直接受脂质调节，因此我们假设刺猬途径可能在NAFLD中失调。我们有选择地操纵在肝细胞和应用的最新方法中平滑的方法，包括单细胞RNA SEQ分析，以确定刺猬信号是否调节肝细胞代谢。值得注意的是，我们发现抑制肝细胞中的刺猬活性足以诱导NaFL并引起许多与NASH发病机理有关的异常。当前的项目评估了NAFLD发病机理的新型概念模型，该模型源自我们的挑衅性新数据，表明肝细胞需要刺猬途径活动，以保护自己免受铁催化的脂质过氧化引起的脂肪毒性应激，并证明由hepatogs the drigs the drig theedde the grig theed the edge theed the grig theed the grig theed the edge the edge the edge the grodprody的损失，包括过度繁殖，这些疾病的损失，包括过度繁殖的疾病。刺猬响应性基质细胞中的不良适应性修复反应。成功完成我们的目标将扩大有关NAFLD发病机理的当前范式，并开放了未来发现的新机会，以改善NAFLD的诊断和治疗。