The proposed research sets out to define the regulation and function of BNIP3 as a nutrient-regulated modulator of mitochondrial mass and lipid metabolism in the liver. This work also addresses the consequences of increased mitochondrial mass and steatosis for liver carcinogenesis. This in turn could have significance for the stratification and treatment of liver cancers based on BNIP3 expression levels and lipid content that justify the future use of FASN inhibitors for treatment of hepatocellular carcinoma. Thus the proposed research should provide fundamental mechanistic insight to novel and important signaling pathways in the liver and translational impact for liver cancer. Specifically, n Aim 1 we seek to fully understand the role of BNip3 in mitochondrial homeostasis and liver metabolism and propose to do so by investigating: (1) why it is important to induce mitophagy in the liver in response to fasting; (2) whether BNip3 also promotes closure of the VDAC1 channel in response to fasting through interactions with Bcl-XL and how these distinct functions of BNip3 in liver metabolism are coordinated. The key objective in Aim 2 is to define the mechanism responsible for induction of BNip3 protein levels in the liver in response to fasting and to understand its significance for BNip3 function. BNIP3 has been shown to be epigenetically silenced in the more common and more aggressive sub-type A of human HCC consistent with BNIP3 playing a tumor suppressive role in HCC.
In Aim 3, we propose to test the effect of BNIP3 loss for initiation and progression of liver cancer using mouse models of HCC, human HCC cell lines and primary human tumors samples and relate our findings to the role of BNIP3 in mitophagy and lipid metabolism in the liver defined in Aim 1 and 2.

Public Health Relevance

The proposed research sets out to test the hypothesis that BNIP3 is a novel and hormone-regulated modulator of mitophagy and lipid metabolism in the liver, de-regulation of which has significance for understanding the link between hepatocellular carcinoma and obesity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA200310-05
Application #
9868816
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Drake, Lauren E; Springer, Maya Z; Poole, Logan P et al. (2017) Expanding perspectives on the significance of mitophagy in cancer. Semin Cancer Biol 47:110-124