Featured Publications


Glucose-dependent Partitioning of
Arginineto the Urea cycle Protects ꞵ-cells
from Inflammation

Fu et al., Nature Metabolism 2020

Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms
that determine cellular sensitivity to inflammation are incompletely understood.
Here, we show the contribution of glucose metabolism to inflammation-induced
changes in the survival of pancreatic islet ꞵ-cells.


HCF-1 Regulates De Novo Lipogenesis through
a Nutrient-Sensitive Complex with ChREBP

Lane, Choi et al., Molecular Cell 2019

Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of
de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis. Mechanisms
underlying nutrient modulation of ChREBP are under active investigation. Here we identify host cell factor 1 (HCF-1) as a previously unknown ChREBP-interacting protein that is enriched
in liver biopsies of nonalcoholic steatohepatitis (NASH) patients.

BAD and KATP Channels Regulate Neuron Excitability and Epileptiform Activity
Martinez-Francois et al., eLife 2018

Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion
or alteration ofBad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism,
accompanied by resistanceto acutely induced epileptic seizures.


Differential Contribution of the Mitochondrial Translation Pathway to the Survival of Diffuse 
Large B-cell Lymphoma Subsets

Norberg, Lako et al., Cell Death & Differentiation 2017

Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which
subsets share molecular features revealed by gene expression profiles and metabolic fingerprints.
While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on
mitochondrial energy transduction and nutrient utilization pathways that provide
pro-survival benefits independent of BCR signaling. 


Phospho-BAD BH3 Mimicry Protects
ꞵ Cells and Restores Functional ꞵ Cell
Mass in Diabetes

Ljubic et al., Cell Reports 2015

Strategies that simultaneously enhance the survival and glucose responsiveness of
insulin-producing ꞵ cells will greatly augment ꞵ cell replacement therapies in type 1 diabetes (T1D). We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3) domain of BAD impart ꞵ-cell-autonomous protective
effects in the face of stress stimuli relevant to ꞵ cell demise in T1D.


Regulation of Hepatic Energy Metabolism and Gluconeogenesis by BAD 
Gimenez-Cassina, Garcia-Haro et al, Cell Metabolism 2014

The homeostatic balance of hepatic glucose utilization, storage, and production is exquisitely controlled by hormonal signals and hepatic carbon metabolism during fed
and fasted states. How the liver senses extracellular glucose to cue glucose utilization
versus production is not fully understood. We show that the physiologic balance of hepatic glycolysis and gluconeogenesis is regulated by Bcl-2-associated agonist of cell
death (BAD), a protein with roles in apoptosis and metabolism.

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A phospho-BAD BH3 Helix Activates Glucokinase by A Mechanism Distinct
From That of Allosteric Activators

Szlyk et al., Nature Structural & Molecular Biology 2014

Glucokinase (GK) is a glucose-phosphorylating enzyme that regulates insulin release and hepatic metabolism, and its loss of function is implicated in diabetes pathogenesis.
GK activators (GKAs) are attractive therapeutics in diabetes; however, clinical data
indicate that their benefits can be offset by hypoglycemia, owing to marked allosteric enhancement of the enzyme’s glucose affinity. We show that a phosphomimetic of the
BCL-2 homology 3 (BH3) a-helix derived from human BAD, a GK-binding partner,
increases the enzyme catalytic rate without dramatically changing glucose affinity,
thus providing a new mechanism for pharmacologic activation of GK. 


Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B Cell Lymphoma 
Care, Norberg, Kishan et al., Cancer Cell 2012 

Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The
OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons
into the tricarboxylic acid cycle, and increased glutathione levels. 


BAD-Dependent Regulation of Fuel Metabolism
and KATP Channel Activity Confers Resistance
to Epileptic Seizures

Gimenez-Cassina et al., Neuron 2012

Neuronal excitation can be substantially modulated by alterations in metabolism, as evident from the anticonvulsant effect of diets that reduce glucose utilization and promote ketone body metabolism. We provide genetic evidence that BAD, a protein with dual functions in apoptosis and glucose metab-olism, imparts reciprocal effects on metabolism of glucose and ketone bodies in brain cells. These effects involve phosphoregulation of BAD and are independent of its apoptotic function. 


Dual Role of Proapoptotic BAD in Insulin Secretion and Beta Cell Survival
Danial et al, Nature Medicine, 2008

The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a
physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. 


“The true sign of intelligence is not knowledge but imagination.” 

Albert Einstein