Regulation and function of BNipP3: Modulation of mitophagy and metabolism during the hepatic fed-fasted transition /

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Bibliographic Details
Author / Creator:Beaton, Michelle L., author.
Ann Arbor : ProQuest Dissertations & Theses, 2015
Description:1 electronic resource (195 pages)
Format: E-Resource Dissertations
Local Note:School code: 0330
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Other authors / contributors:University of Chicago. degree granting institution.
Notes:Advisors: Kay F. Macleod Committee members: Matthew Brady; Navdeep Chandel; Christopher Rhodes.
Dissertation Abstracts International, Volume: 77-02(E), Section: B.
Summary:The work presented here demonstrates a novel hepatic nutrient sensing pathway mediated by BNip3 that is required to induce mitophagy and limit lipid synthesis in response to nutrient deprivation. BNip3 is a mitochondrial protein that promotes mitochondrial turnover during the process of mitophagy, a specialized form of autophagy in which mitochondria are selectively degraded via autophagic engulfment and subsequent degradation at the lysosome. Hepatic mitophagy was first observed in 1967 by Christian de Duve, however, the underlying molecular mechanism of glucagon-induced mitophagy in the liver is still unclear.
We previously showed that BNip3 null mice exhibit diminished hepatic glucose production after overnight fasting and also develop hepatic steatosis that is associated with increased mitochondrial mass. Because glucagon signaling plays a key role in regulating the responses of the liver to fasting and BNip3 promotes mitophagy, we set out to test whether BNip3 is required for hepatic mitophagy in response to fasting and furthermore determine how BNip3 protein levels and function are regulated by glucagon in the fasted liver. Here, we show that BNIP3 is rapidly induced upon fasting or intra-peritoneal injection of glucagon and is required for glucagon-induced mitophagy in adult mouse liver. We also show that BNip3 is a direct target of protein kinase A (PKA), resulting in BNip3 stabilization in vivo. BNip3 null mice develop hepatic steatosis, but interestingly, the expression of either wild-type or mitophagy deficient BNip3 is able to reduce lipid accumulation in BNip3 null liver, suggesting that BNip3 has an additional mitophagy-independent role in lipid metabolism.