Significance and mechanisms of hepatic ChREBPα induction via post-translational modifications in diet-induced NASH

摘要 NAFLD是最常见的慢性肝病，影响10-30%的普通人群。其 从单纯性脂肪变性向非酒精性脂肪性肝炎（NASH）的转变对健康构成严重威胁。 由于最终进展为肝硬化和肝功能衰竭而造成的威胁。鉴于肝脏 移植是NASH终末期患者的唯一治疗选择，因此迫切需要一种新的治疗方法。 需要了解NASH发展的分子机制。到目前为止， 人类和动物研究都表明，肝脏中FAO的长期抑制 可能是促进脂肪肝疾病的关键驱动因素。与此同时，不受控制的激活 肝星状细胞（HSCs）已被确定为肝纤维化的主要来源。 然而，关于是否以及如何调节失调， 肝脂肪酸氧化促进NASH。此外，肝脂质调节剂是否以及如何 导致HSC活化和肝纤维化的原因尚不清楚。我们收集了证据 肝脏ChREBPα作为脂肪酸氧化新调节剂，与其作为 脂肪生成转录因子肝细胞特异性ChREBPα敲除小鼠更敏感 饮食诱导的NASH，而肝脏过表达ChREBPα保护小鼠免受 饮食诱导的NASH。我们的RNA-seq分析显示，Chrebpα的肝缺乏升高了 用NASH饮食喂养后小鼠肝脏中的一组促纤维化因子。我们的体外 实验进一步证明，Chrebpα缺陷肝细胞刺激肝纤维化， 人肝星状细胞通过分泌因子，提示肝细胞ChREBPα可以 影响肝星状细胞周围的微环境并调节其活性。 基于这些有趣的观察结果，我们假设肝细胞ChREBPα可以保护 通过促进肝细胞中的脂肪酸氧化来对抗饮食诱导的NAFLD/NASH， 抑制肝星状细胞活化。在这项研究中，我们建议测试我们的假设， 三个目的：目的1是检测肝脏Chrebpα是否保护饮食诱导的 NAFLD/NASH通过维持脂肪酸氧化途径。目标2是确定是否 肝细胞ChREBPα通过分泌促纤维化因子抑制肝星状细胞活化 因素目的3是研究ChREBPα的信号转导和降解途径 在NASH期间的表达和活性。建议的研究完成后，将可澄清─ 深入探讨ChREBPα如何防止饮食诱导的NASH的分子机制， ChREBPα相关的风险因素，并阐明了预防和治疗的新策略。 治疗饮食诱导的NASH。

Abstract NAFLD is the most common chronic liver disease affecting 10-30% of the general population. Its transition from simple steatosis to non-alcoholic steatohepatitis (NASH) poses a serious health threat due to the eventual progression to cirrhosis and liver failure. Given the fact that liver transplant is the only treatment option for patients at the end stage of NASH, there is an urgent need to understand the molecular mechanisms underlying the development of NASH. So far, both human and animal studies have suggested that chronic suppression of FAO in the liver could be a critical driver in promoting fatty liver disease. Meanwhile, uncontrolled activation of hepatic stellate cells (HSCs) has been identified as the primary source of hepatic fibrogenesis. However, there is a significant knowledge gap regarding whether and how dysregulation of hepatic fatty acid oxidation promotes NASH. Moreover, whether and how hepatic lipid regulators contribute to HSCs activation and liver fibrosis remains unknown. We have gathered evidence hepatic ChREBPα as a novel regulator of fatty acid oxidation in contrast to its canonical role as lipogenic transcriptional factor. Hepatocyte-specific ChREBPα knockout mice are more sensitive to diet induced NASH, whereas hepatic over-expression of ChREBPα protects mice against diet-induced NASH. Our RNA-seq analysis revealed that hepatic deficiency of Chrebpα elevates a panel of pro-fibrogenic factors in the mouse liver after feeding with NASH diet. Our in vitro experiments further demonstrated that Chrebpα-deficient hepatocytes stimulate fibrogenesis of human hepatic stellate cells via secreting factors, suggesting that hepatocyte ChREBPα could influence the microenvironment around hepatic stellate cells and modulate their activities. Based on these intriguing observations, we hypothesize that hepatocyte ChREBPα protects against diet-induced NAFLD/NASH by promoting fatty acid oxidation in hepatocytes and suppressing hepatic stellate cells activation. In this study, we propose to test our hypothesis in three aims: Aim 1 is to examine whether hepatic Chrebpα protects against diet-induced NAFLD/NASH via maintaining fatty acid oxidation pathway. Aim 2 is to determine whether hepatocyte ChREBPα suppresses hepatic stellate cell activation via secreting profibrogenic factors. Aim 3 is to dissect out the signaling and degradation pathways that control ChREBPα expression and activity during NASH. The completion of the proposed study would elucidate in- depth molecular mechanisms of how ChREBPα protects against diet-induced NASH, identify ChREBPα-associated risk factors, and shed light on novel strategies for the prevention and treatment diet-induced NASH.