Hepatic Lipotoxicity, Metabolic Homeostasis and NAFLD Pathogenesis

修改后的项目摘要/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，并构成主要的公共健康威胁和经济负担，因为它可导致肝硬变和肝癌。这些不良结局主要发生在脂肪肝患者，他们出现肝细胞损伤(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。预防和治疗NAFLD相关的肝硬变和肝癌一直受到控制NASH易感性的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不适应的。该项目评估了肝细胞刺猬活性控制NASH(脂毒性)和NASH肝硬变(适应不良修复)易感性的一般假设。Hedgehog是一种在胚胎中协调肝脏发育的形态发生信号通路。它被认为在成人肝细胞中是沉默的，但新出现的证据表明，它在成人肝脏中的肝细胞亚群中仍然活跃。由于Smoothens(Hedgehog途径的关键成分)直接受脂质调节，我们推测Hedgehog途径可能在NAFLD中调节失调。我们选择性地操纵了肝细胞中的Smomoothated，并应用了最先进的方法，包括单细胞RNA序列分析，以确定Hedgehog信号是否/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发病机制的一个新的概念模型，该模型源自我们具有挑衅性的新数据，该数据表明，肝细胞需要Hedgehog途径的活性来保护自己免受铁催化的脂质过氧化引起的脂毒应激，并且有证据表明，肝细胞中Hedgehog信号的丢失会触发代偿性反应，包括Hedgehog配体的过度产生，从而驱动Hedgehog反应性基质细胞的不良适应修复反应。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，并为未来发现改进NAFLD的诊断和治疗打开新的机会。

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.