BNip3 is a hypoxia-inducible member of the Bcl-2 family that integrates into the outer mitochondrial membrane as stable homodimers where it acts as a receptor for mitochondrial engulfment through a conserved LC3 interacting region. Hepatic BNip3 levels are constitutively elevated relative to other tissues, and dramatically increase upon nutrient deprivation or glucagon stimulation, suggesting a key role for BNip3 in the fasting response. We have determined that the fasting-induced increase in hepatic BNip3 protein levels is not solely attributable to transcriptional induction and have identified post-translational modification of BNip3 that affects protein stability and function. In a mouse model of BNip3 loss, we observe metabolic defects including increased hepatic lipid synthesis and reduced fatty acid oxidation. Consistent with BNip3's role in mitophagy, defects in liver metabolism were linked to increased mitochondrial mass, but decreased mitochondrial function, including reduced oxygen consumption and loss of mitochondrial membrane potential. Delivery of a mitophagy deficient mutant BNip3 to the BNip3 null liver indicates that defects in lipid metabolism are not simply due to the accumulation of defective mitochondria, but rather BNip3 has another role to regulate lipid metabolism based on nutrient status. Of relevance, BNip3 is epigenetically silenced in the more aggressive and common form of HCC (sub-type A) and thus this work identifies potential mechanisms by which this protein may act as a tumor suppressor. Citation Format: Michelle L. Boland, He Huang, Ramilla Shah, Almas Ali, Yingming Zhao, Christopher J. Rhodes, Kay F. Macleod. BNip3 connects energy sensing to hepatic lipid metabolism and mitophagy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4324. doi:10.1158/1538-7445.AM2014-4324
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