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

摘要 非酒精性脂肪肝是最常见的慢性肝病，占总人口的10%-30%。它的 从单纯性脂肪变性到非酒精性脂肪性肝炎(NASH)的转变构成了严重的健康 由于最终进展为肝硬变和肝功能衰竭而造成的威胁。考虑到肝脏 移植是终末期NASH患者的唯一治疗选择，有急迫的 需要了解NASH发生的分子机制。到目前为止, 人类和动物研究都表明，粮农组织在肝脏中的慢性抑制 可能是促进脂肪肝的关键驱动因素。与此同时，不受控制的激活 肝星状细胞(HSCs)是肝纤维化的主要来源。 然而，在是否以及如何监管失调方面，存在着显著的知识差距。 肝脏脂肪酸氧化促进NASH。此外，肝脂调节剂是否以及如何 对HSCs激活和肝纤维化的作用尚不清楚。我们已经收集了证据 肝脏ChREBPα作为一种新的脂肪酸氧化调节剂与其典型作用的对比 生脂转录因子。肝细胞特异性ChREBPα基因敲除小鼠更敏感 对饮食诱导的NASH，而肝脏过表达ChREBPα则保护小鼠免受 饮食诱导的NASH。我们的rna-seq分析显示，ChREBPα的肝脏缺陷会升高。 喂食纳什饮食后小鼠肝脏中的一组促纤维化因子。我们的体外培养 实验进一步证明ChREBPα缺陷的肝细胞可促进肝纤维化的形成。 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，调节其活动。 基于这些有趣的观察，我们假设肝细胞ChREBPα保护 通过促进肝细胞脂肪酸氧化和抗饮食诱导的NAFLD/NASH 抑制肝星状细胞活化。在这项研究中，我们建议检验我们的假设在 三个目的：目的1是研究肝脏ChREBPα是否对饮食诱导有保护作用 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通过分泌纤维原抑制肝星状细胞活化 各种因素。目标3是剖析控制ChREBPα的信号和降解途径 在NASH过程中的表达和活性。建议的研究完成后，将可澄清以下事项： ChREBPα如何预防饮食诱导的NASH的深入分子机制，鉴定 ChREBPα相关危险因素，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.