Hepatic Lipotoxicity, Metabolic Homeostasis and NAFLD Pathogenesis

肝脏脂毒性、代谢稳态和 NAFLD 发病机制

• 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
• 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

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.

修改项目摘要/摘要部分 非酒精性脂肪性肝病（NAFLD）困扰着三分之一的成年人，并构成了重大的公共卫生威胁和经济负担，因为它可以导致肝硬化和肝癌。 这些不良结局主要发生在发生肝细胞损伤（脂毒性）和非酒精性脂肪性肝炎（NASH）但随后出现适应不良修复反应的脂肪肝患者中。预防和治疗NAFLD相关的肝硬化和肝癌受到控制NASH易感性机制的知识空白的限制，这些机制决定了修复NASH的反应是有效的还是适应不良的。 该项目评估了肝细胞Hedgehog活性控制NASH（脂毒性）和NASH肝硬化（适应不良修复）易感性的一般假设。 Hedgehog是一种形态发生信号通路，在胚胎中协调肝脏发育。它被认为在成年肝细胞中沉默，但新出现的证据表明，它在成年肝脏的肝细胞亚群中仍然具有活性。 由于Smoothened（Hedgehog通路的关键组分）直接受脂质调节，我们推测Hedgehog通路可能在NAFLD中失调。 我们在肝细胞中选择性地操纵Smoothened，并应用最先进的方法，包括单细胞RNA测序分析，以确定Hedgehog信号传导是否/如何调节肝细胞代谢。值得注意的是，我们发现抑制肝细胞中的Hedgehog活性足以诱导NAFL并引起许多与NASH发病机制有关的异常。 目前的项目评估了NAFLD发病机制的一种新的概念模型，该模型来源于我们的挑衅性新数据，这些数据表明肝细胞需要Hedgehog通路活性来保护自己免受铁催化的脂质过氧化引起的脂毒性应激，并证明肝细胞中Hedgehog信号转导的丧失引发了代偿反应，包括Hedgehog配体的过度产生，这驱动了Hedgehog反应性基质细胞的适应不良修复反应。我们的目标的成功完成将拓宽目前关于NAFLD发病机制的范例，并为未来发现改善NAFLD诊断和治疗开辟新的机会。