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

点击翻译按钮获取中文摘要

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.