Regulation of Hepatic Fuel Utilization and Storage Through BAD-Dependent Glucose Signaling
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CitationLane, Elizabeth. 2018. Regulation of Hepatic Fuel Utilization and Storage Through BAD-Dependent Glucose Signaling. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractMetabolic adaptation to fed and fasted states is intricately controlled by nutrient and hormonal signals. In the fed state, the liver stores glucose first as glycogen and then converts excess glucose to fat through de novo lipogenesis (DNL). During fasting, the liver produces glucose first though glycogen breakdown and then through de novo synthesis, a process known as gluconeogenesis, which is coupled to fatty acid oxidation. When dysregulated, these processes can lead to metabolic disorders such as diabetes and fatty liver disease.
In the liver, the glucose-phosphorylating enzyme glucokinase (GK) is a key regulator of the balance between glycolysis and gluconeogenesis, and the attendant changes in fat metabolism. Hepatic GK is modulated by hormonal and nutrient signals, including multiple regulatory proteins. Here we investigated the relevance of the BCL2-associated agonist of cell death (BAD), a protein that activates GK when phosphorylated at serine 155 residue in response to glucose and insulin. We demonstrate that loss of BAD reprograms hepatic metabolism towards diminished glycolysis and DNL, increased fatty acid oxidation, and exaggerated gluconeogenesis that escapes suppression by insulin. These metabolic alterations are rescued by reconstitution with a GK-activating phosphomimic variant of BAD. Conversely, loss of GK ablates the capacity of phospho-BAD to regulate hepatic substrate metabolism, indicating that GK mediates BAD’s function in the liver. We further show that BAD’s effects on DNL are mediated by the Carbohydrate Response Element Binding Protein (ChREBP), a key transcription factor regulating hepatic DNL in response to glucose stimulation. We identified a novel ChREBP-interacting protein that recruits GlcNAc transferase (OGT) to ChREBP, promoting ChREBP O-GlcNAcylation and activity. Deletion of GK or BAD leads to diminished hexosamine biosynthesis, OGT recruitment to ChREBP, ChREBP O-GlcNAcylation, and lipogenic gene expression in response to glucose. Remarkably, these changes can be rescued by GlcNAc supplementation. The physiologic relevance of BAD’s effect on hepatic metabolism is evident from the ability of a BAD phosphomimic variant to counteract unrestrained gluconeogenesis and improve glycemia in leptin-resistant and high fat diet models of diabetes and insulin resistance, and by altered BAD phosphorylation in liver biopsies of patients with fatty liver disease.
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