title: BNip3 regulates mitochondrial function and lipid metabolism in the liver.
abstract: BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. While the BNip3 protein is constitutively expressed in adult liver from fed mice, we have shown that its expression is superinduced by fasting of mice, consistent with a role in responses to nutrient deprivation. Loss of BNip3 resulted in increased lipid synthesis in the liver that was associated with elevated ATP levels, reduced AMP-regulated kinase (AMPK) activity, and increased expression of lipogenic enzymes. Conversely, there was reduced β-oxidation of fatty acids in BNip3 null liver and also defective glucose output under fasting conditions. These metabolic defects in BNip3 null liver were linked to increased mitochondrial mass and increased hepatocellular respiration in the presence of glucose. However, despite elevated mitochondrial mass, an increased proportion of mitochondria exhibited loss of mitochondrial membrane potential, abnormal structure, and reduced oxygen consumption. Elevated reactive oxygen species, inflammation, and features of steatohepatitis were also observed in the livers of BNip3 null mice. These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver that has consequences for lipid metabolism and disease.
authors.affiliation: Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Glick
authors.forename: Wenshuo
authors.initials: W
authors.lastname: Zhang
authors.forename: Michelle
authors.initials: M
authors.lastname: Beaton
authors.forename: Glenn
authors.initials: G
authors.lastname: Marsboom
authors.forename: Michaela
authors.initials: M
authors.lastname: Gruber
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brady
authors.forename: Kay F
authors.initials: KF
authors.lastname: Macleod
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005215:Fasting / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D050155:Lipogenesis; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D010101:Oxygen Consumption
chemical_list: C508686:BNip3 protein, mouse; D005227:Fatty Acids; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose