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Branched Chain Amino Acids and Human Disease

WEBINAR

Only

Branched Chain Amino Acids and Human Disease

Thursday, May 14, 2020, 12:00 PM - 5:05 PM EDT

Recent clinical and preclinical studies have implicated altered branched chain amino acid (BCAA) metabolism in multiple diseases including diabetes/metabolic syndrome, heart failure, and cancer. However, many unknowns remain, including the mechanisms underlying the alterations in BCAA catabolism, how this dysfunction leads to disease, and whether aberrant BCAA metabolism is causal to or merely a consequence of disease. This symposium will bring together multidisciplinary scientists to review the landscape of what is known about BCAA metabolism in various systems, discuss knowledge gaps, and identify potential therapeutic nodes of intervention to ameliorate human diseases.

Registration

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$30
Nonmember Academia, Faculty, etc.
$65
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$85
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$65
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$45
Member Student, Post-Doc, Fellow
$15
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Scientific Organizing Committee

Zoltan Arany
Zoltan Arany, MD, PhD

University of Pennsylvania

Michelle Clasquin
Michelle Clasquin, PhD

Pfizer

Kevin Filipski
Kevin Filipski, PhD

Pfizer

Rachel Roth Flach
Rachel Roth Flach, PhD

Pfizer

Claire Steppan
Claire Steppan, PhD

Pfizer

Yibin Wang, PhD
Yibin Wang, PhD

UCLA

Sonya Dougal
Sonya Dougal, PhD

New York Academy of Sciences

Kari Fischer
Kari Fischer, PhD

New York Academy of Sciences

Speakers

Tracy Anthony, PhD
Tracy Anthony, PhD

Rutgers University

Zoltan Arany, MD, PhD
Zoltan Arany, MD, PhD

University of Pennsylvania

David Chuang
David Chuang, PhD

University of Texas Southwestern Medical Center

Christian Metallo
Christian Metallo, PhD

University of California, San Diego

Christopher Newgard
Christopher Newgard, PhD

Duke University Medical Center

Rachel Roth Flach, PhD
Rachel Roth Flach, PhD

Pfizer

Rong Tian
Rong Tian, MD, PhD

University of Washington

Yibin Wang
Yibin Wang, PhD

UCLA

Program Supporters



Thursday

May 14, 2020

12:00 PM

Introduction and Welcome Remarks

Speaker

Kari Fischer, PhD
New York Academy of Sciences

Session 1: Fundamentals of BCAA Metabolism

12:15 PM

Branched Chain Amino Acids and Glucose Metabolism

Speaker

Rong Tian, PhD
University of Washington

My research focuses on the molecular mechanisms regulating cell metabolism and energetics. A longterm goal of my laboratory is to understand the role of mitochondria and metabolism in the pathogenesis of human diseases, in particular cardiovascular diseases. We have utilized molecular and genetic approaches to identify and perturb specific regulators in the key pathways of cardiac energy metabolism in mice and subsequently interrogated the physiological and biochemical responses in vivo during the development of heart failure using multi-nuclear NMR spectroscopy. Our work in the past two decades focused on the oxidative metabolism and mitochondrial ATP synthesis in heart failure using mouse models of altered glucose and fatty acid metabolism in the heart. Our recent work investigates the signaling role of cell metabolism through energy dependent and independent mechanisms. We also seek to decipher the mechanistic link between impaired mitochondrial function the cardiac stress responses. Results of these studies identified an important role of cellular redox state in diseases caused by mitochondrial dysfunction including cardiovascular and neurological pathologies.

12:45 PM

Tracing the Metabolic Fate of Branched Chain Amino Acids in Obesity

Speaker

Christian M. Metallo, PhD
University of California, San Diego

Metabolism is central to virtually all cellular functions and contributes to a range of diseases. A quantitative understanding of how biochemical pathways are dysregulated in the context of diseases such as cancer, metabolic syndrome, and neuropathy is necessary to identify new therapeutic targets. To this end we apply stable isotope tracers, mass spectrometry, and metabolic flux analysis (MFA) to study metabolism in mammalian cells, animal models, and human patients. We are particularly interested in understanding how alterations in amino acid metabolism influence lipid diversity and cellular function. We have performed quantitative analyses on the fate of BCAAs across mouse tissues in the context of obesity. By linking these results to parallel studies on lipogenesis, we have elucidated the origin of branched-chain amino acid (BCAA)-derived monomethyl branched-chain fatty acids (mmBCFAs) in mammals. These fatty acids are synthesized by adipose tissue via promiscuous activity of CrAT and FASN, and their abundance changes dramatically in response to obesity. Cellular studies have enabled us to identify adipose tissue hypoxia as a key driver that influences BCAA catabolism and alters the lipidome. These studies provide mechanistic insights into why BCAAs are altered in obese individuals and how enzyme promiscuity can influence lipid diversity.

1:15 PM

Break

1:25 PM

Tissue-Specific Impact of BCAA Regulation: Insights from Genetic Models

Speaker

Yibin Wang, PhD
UCLA

Branched-Chain Amino Acids (BCAAs) are essential amino acids with highly regulated systemic homeostasis in animals.  Over the past decade, elevated plasma and tissue levels of BCAA or their metabolites are identified to be strongly associated with diabetes and cardiovascular diseases. Earlier studies have also demonstrated that targeted and systemic intervention of BCAA catabolic pathway confers significant therapeutic benefits to alleviate insulin resistance and heart diseases. However, much of the pathophysiological mechanism and molecular/cellular basis of the therapeutic effects remain unexplored.  It is particular intriguing that tissue-specific contribution to the systemic manifestation of BCAA catabolic defects observed in diabetes and obesity, and cell-autonomous effect of BCAA catabolic regulation on target organ function such as heart, liver, skeletal muscle and fat are largely unknown.  Utilizing genome editing techniques, we generated mice carrying floxed alleles for either the branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK) or the BCKD E1a (BCKDHA) subunit genes to achieve tissue-specific activation or inhibition of BCAA catabolic activities.  The preliminary analysis shows cardiomyocyte specific and inducible KO of BCKDHA in adult hearts triggered significant and sustained cardiac dysfunction, accompanied by changes in stress-response genes and metabolic genes. However, cardiac specific KO BCKDK did not confer significant protection against pressure-overload induced cardiac hypertrophy or heart failure. On the other hand, adipose specific KO of BCKDK significantly affected adipogenesis, impaired thermogenesis and adipose mitochondrial function while BCKDHA adipose KO did not trigger or worsen high fat diet induced obesity and insulin resistance.  These results demonstrate that normal cell-autonomous BCAA regulation is critical to maintain cardiac function and adipose tissue thermogenic activity.  However, the therapeutic effect of BCKDK inhibition for heart failure and diabetes may require additional contribution from non-cardiac or non-adipose tissues, respectively. Overall, our study showcases the importance of inter-organ interactions for BCAA catabolic homeostasis and for the pathogenesis of diabetes and heart failure.

Session 2: Translating BCAA Metabolism for Human Disease

1:55 PM

Towards Developing Specific Inhibitors for BCKD Kinase

Speaker

David Chuang, PhD
University of Texas Southwestern Medical Center

The mitochondrial branched-chain alpha-keto acid dehydrogenase complex (BCKDC) catalyzes the rate-limiting step in the degradation of branched-chain amino acids (BCAAs) leucine, isoleucine and valine. The BCKD kinase (BDK) that phosphorylates and inactivates BCKDC is upregulated in cardiometabolic diseases, resulting in elevated BCAAs and the corresponding alpha-keto acids (BCKAs). We show that a designer BDK inhibitor (S)-α-chloro-phenylpropionic acid [(S)-CPP] binds to an allosteric site in the N-terminal domain of BDK subunit. The bound ligand triggers large helix movements that restrict access of the BCKD decarboxylase (E1) substrate to the active-site, thereby inactivating BDK. To target BDK for cardiometabolic diseases, a specific BDK inhibitor 3, 6-dichloro[b]thiophene-2-carboxylic acid (BT2) was isolated by high-throughput screening. BT2 binds to the same site as (S)-CPP with similar mechanisms for BDK inactivation. BT2 shows favorable pharmacokinetic properties (terminal T1/2 = 730 min) and excellent metabolic stability. Oral administration of BT2 to ob/ob and diet-induced obese mice reduces circulating BCAA/BCKA levels with markedly improved glucose and insulin tolerance. Moreover, increased BCAA oxidation by BT2 significantly mitigates reactive oxygen species production and blunts cardiac dysfunction after pressure overload. These results provide a proof-of-concept for targeting BDK as a novel therapeutic approach to obesity, insulin resistance and heart failure.

Coauthor: R. Max Wynn, University of Texas Southwestern Medical Center.

2:25 PM

Break

2:55 PM

Branched Chain Amino Acid Deficiency and Neurological Diseases

Speaker

Tracy Anthony, PhD
Rutgers University

Branched-chain amino acid (BCAA) catabolism is regulated by branched-chain keto acid dehydrogenase
(BCKD), an enzyme complex that is inhibited when phosphorylated by its kinase (BCKDK). Genetic
defects regulating the breakdown of the BCAAs by BCKD are linked to neurological diseases in humans
and rodents. Specifically, loss of BCKDK function in mice and humans causes BCAA deficiency and
intellectual disability with epilepsy and autistic features. My laboratory has explored the signal
transduction mechanisms responsive to BCAA deficiency in the brain and examined why genetic BCAA
deficiency results in neurobehavioral impairments. These efforts have identified the amino acid sensing
kinase, general control nonderepressible 2 (GCN2) as protective during chronic BCAA deficiency. Mice
lacking both Bckdk and Gcn2 are born normal in size and appearance but fail to thrive soon after birth,
displaying defects in neurological function and locomotor control, culminating in early death due to a fatal
leukodystrophy. These outcomes reveal a vital role for BCAA metabolism and its proper regulation in
neurological development. The need for a deeper understanding of how BCAA metabolism is connected
to neurological processes will be discussed as necessary to develop new approaches and treatments for
neurological diseases.

3:25 PM

BCAAs in Insulin Resistance and Heart Failure

Speaker

Zoltan Arany, PhD
University of Pennsylvania
3:55 PM

Break

4:05 PM

Linking Control of BCAA Metabolism to Cardiometabolic Disease Pathogenesis

Speaker

Christopher B. Newgard, PhD
Duke University Medical Center

We use multi-omics technologies to investigate metabolic regulatory mechanisms underlying development of cardiometabolic disease phenotypes. Our work has identified a metabolomic signature of perturbed branched chain amino acid (BCAA) catabolism that is associated with cardiometabolic diseases, predictive of intervention outcomes, and highly responsive to the most efficacious interventions for obesity and diabetes. BCAA restriction in Zucker fatty rats (ZFR) improves insulin sensitivity, and tissue metabolic profiling demonstrates that relief of mitochondrial fuel overload serves as a contributing mechanism for this effect. Metabolic flux analysis (“fluxomics”) demonstrates dynamic reciprocal regulation of tissue glycine levels in response to changes in BCAA, serving to relieve muscle nitrogen burden and export incompletely oxidized acyl CoAs out of muscle tissue in the form of glycine adducts. To investigate the impact of manipulation of BCAA catabolism, we have used small molecule inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulate activity of the branched-chain ketoacid dehydrogenase (BCKDH) complex. Manipulation of BDK or PPM1K to activate BCKDH improves glucose, lipid and amino acid homeostasis in ZFR, including enhancement of insulin sensitivity and lowering of liver triglycerides. Phosphoproteomic analysis identified ATP-citrate lyase (ACL) as an alternative BDK/PPM1K substrate. Overexpression of BDK is sufficient to phosphorylate and activate ACL, leading to increased hepatic de novo lipogenesis. Finally, transcriptomic profiling reveals that BDK is upregulated and PPM1K downregulated by fructose feeding and the ChREBP- transcription factor. These studies identify a new ChREBP-regulated mechanism that links BCAA, glucose and lipid metabolism. Manipulation of this node reverses several obesity-associated metabolic disease phenotypes.

Reference: White, P. and Newgard, CB. 2019. "Branched-chain amino acids in disease." Science 363:882-583.

Coauthors: Robert McGarrah, Mark Herman, and Phillip White, Duke Molecular Physiology Institute, Duke University Medical Center.

4:35 PM

BCKD Kinase Inhibition Improves Cardiac Function and Hypertrophy in a Rodent HFpEF Model

Speaker

Rachel Roth Flach, PhD
Pfizer

Circulating increases in branched chain amino acid (BCAA) levels have long been associated with type II diabetes and metabolic syndrome. Emerging data also suggest that BCAA catabolism may play a role in heart failure progression. It is hypothesized that decreased catabolism, rather than increased consumption of BCAAs, is responsible for these correlations. Branched chain ketoacid (BCKA) dehydrogenase kinase (BDK) is a negative regulator of BCAA catabolism. Several labs have published functional improvements using the BDK inhibitor molecule BT2 in rodent heart failure models. Here, we demonstrate a reduction of BCAA, BCKA and heart tissue p-BCKDH and BDK levels concomitant with improved heart function in a Dahl Salt Sensitive rat model of heart failure after BT2 treatment. We utilized a diet induced obesity mouse model to further understand how BDK inhibition leads to improved heart function by performing phospho-proteomic analysis and RNAseq in isolated mouse tissues. As expected, the phospho-proteomic analysis identified p-BCKDH as the most significantly regulated phospho site after BT2 treatment. Furthermore, RNAseq analysis identified several metabolic pathways that may be important for the preservation of cardiac function.

Coauthors: Eliza Bollinger, Jenna Libera, Liam Hurley, Dinesh Hirenallur Shanthappa, Xian Chen, Terri Swanson, C. Parker Siddall, Susanne Breitkopf, Mara Monetti, Arun Shipstone, Angela Hadjipanayis, Allyson McGuinty, Michael Nagle, Evanthia Pashos, Liang Xue, Brendan Tierney, Natalie Daurio, Ka Ning Yip, Bei B. Zhang, and Russell Miller; Internal Medicine Research Unit, Pfizer Inc.

5:05 PM

Meeting Concludes

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