BNIP3 and BNIP3L (NIX) in lipid homeostasis and growth control in the liver

项目摘要 脂肪肝已成为肝细胞性肝癌发病率增加的主要因素， 在过去的几年里，西方社会的肝癌（HCC），以及美国的HCC发病率预计 由于营养过剩和肥胖症的流行，在未来几年中，这一数字将进一步增加。因此， 了解肝脏中的脂质水平是如何调节的，以及脂质的潜在机制基础 在疾病状态下的积累对于开发预防和治疗脂肪肝的改进方法是重要的 和HCC。这项拟议的研究旨在确定BNIP3和BNIP3L线粒体的作用， 货物受体在正常肝脏的脂质代谢中的作用以及在预防脂肪肝疾病和肝细胞癌中的作用 carcinoma.在该基金的上一个周期中，我们发现BNIP3对于由BNIP3诱导的线粒体自噬是必不可少的。 营养缺乏，这反过来又促进了脂滴周转。此外，我们发现BNIP3- 依赖性线粒体自噬通过控制线粒体质量在肝脏中建立代谢分区。我们 也表明BNIP3的缺失由于两种小鼠肝脏模型中的脂质积累而促进HCC 在肝癌和人肝中，BNIP3表达的缺失预测了HCC患者的结果， 与参与脂肪酸代谢的基因的表达水平相结合。在这次更新申请中， 我们的工作旨在进一步发展我们对BNIP3如何促进脂质代谢的机制基础的理解。 液滴的周转与线粒体的周转一致，BNIP3在线粒体中的第二个新作用是什么？ 调节mTOR信号通路有助于NAFLD和NASH进展为HCC， BNIP3和BNIP3L（NIX）在肝脏中如何相互作用。具体而言，在目标1中，我们力求充分 了解BNIP3在脂滴周转和肝脏代谢中的作用，通过调查：（1）是否 BNIP3在溶酶体和脂滴处与Rheb或其他分子伴侣相互作用;和/或（2）如何 Rheb-BNIP3相互作用调节BNIP3-LC3相互作用和线粒体自噬。Aim中的关键目标 2是定义BNIP3如何通过调节mTOR通路信号传导来抑制脂肪变性和HCC。在 目的3，我们建议确定BNIP3和BNIP3L（NIX）在肝脂肪变性中的作用如何不同， 这如何有助于控制脂肪变性、mTOR活性、肿瘤细胞生长和肝癌。在整个 在这项更新建议中，我们利用了新的小鼠模型、人HCC细胞系和原代人肝癌细胞系。 肝脏样品中的BNIP3和BNIP3L的脂质稳态和生长控制中的肝脏解释的作用。

Project Summary Fatty liver disease has emerged as a major contributing factor to the increased incidence of hepatocellular carcinoma (HCC) in western societies in the past several years, and rates of HCC in the US are projected to increase further in the years ahead due to over-nutrition and the obesity epidemic. Thus, an understanding of how lipid levels in the liver are regulated and the underlying mechanistic basis of lipid accumulation in disease states is important to developing improved ways to prevent and treat fatty liver and HCC. The proposed research sets out to define the role of the BNIP3 and BNIP3L mitochondrial cargo receptors in lipid metabolism in normal liver and in preventing fatty liver disease and hepatocellular carcinoma. In the past cycle of this grant, we showed that BNIP3 is essential for mitophagy induced by nutrient deprivation and that this in turn promotes lipid droplet turnover. Further, we showed that BNIP3- dependent mitophagy sets up metabolic zonation in the liver through control of mitochondrial mass. We also showed that loss of BNIP3 promoted HCC due to lipid accumulation in both mouse models of liver cancer and in human liver, where loss of BNIP3 expression predicted HCC patient outcomes when combined with expression levels of genes involved in fatty acid metabolism. In this renewal application, our work aims to develop further our understanding of the mechanistic basis of how BNIP3 promotes lipid droplet turnover in concert with the turnover of mitochondria, how a second novel role for BNIP3 in modulating the mTOR signaling pathway contributes to progression of NAFLD and NASH to HCC, and how BNIP3 and BNIP3L (NIX) interact functionally in the liver. Specifically, in Aim 1 we seek to fully understand the role of BNIP3 in lipid droplet turnover and liver metabolism by investigating: (1) whether BNIP3 interacts with Rheb or other molecular partners at the lysosome and lipid droplet; and/or (2) how the Rheb-BNIP3 interaction modulates BNIP3-LC3 interactions and mitophagy. The key objective in Aim 2 is to define how BNIP3 suppresses steatosis and HCC via modulation of mTOR pathway signaling. In Aim 3, we propose to determine how BNIP3 and BNIP3L (NIX) differ in their role in hepatic steatosis and how this contributes to control of steatosis, mTOR activity, tumor cell growth and liver cancer. Throughout this renewal proposal, we make use of novel mouse models, human HCC cell lines and primary human liver samples to explain the role of BNIP3 and BNIP3L in lipid homeostasis and growth control in the liver.