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Branched Chain Amino Acids and Human Disease

Branched Chain Amino Acids and Human Disease

Thursday, March 19, 2020

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

Presented By

The Biochemical Pharmacology Discussion Group

The New York Academy of Sciences

 

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

Member
By 02/06/2020
$90
After 02/06/2020
$130
Nonmember Academia, Faculty, etc.
By 02/06/2020
$180
After 02/06/2020
$260
Nonmember Corporate, Other
By 02/06/2020
$250
After 02/06/2020
$350
Nonmember Not for Profit
By 02/06/2020
$180
After 02/06/2020
$260
Nonmember Student, Undergrad, Grad, Fellow
By 02/06/2020
$100
After 02/06/2020
$145
Member Student, Post-Doc, Fellow
By 02/06/2020
$50
After 02/06/2020
$70
Earlybird Registration:
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Deadline:
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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, PhD
Claire Steppan, PhD

Pfizer

Yibin Wang
Yibin Wang, PhD

University of California, Los Angeles

Sonya Dougal, PhD
Sonya Dougal, PhD

New York Academy of Sciences

Kari Fischer, PhD
Kari Fischer, PhD

New York Academy of Sciences

Keynote Speaker

Susan Hutson, PhD

Virginia Tech

Speakers

Tracy Anthony
Tracy Anthony, PhD

Rutgers University

Zoltan Arany
Zoltan Arany, MD, PhD

University of Pennsylvania

David Chuang
David Chuang, PhD

UT Southwestern

Christian Metallo
Christian Metallo, PhD

University of California, San Diego

Christopher Newgard
Christopher Newgard, PhD

Duke University

Rachel Roth Flach
Rachel Roth Flach, PhD

Pfizer

Rong Tian
Rong Tian, MD, PhD

University of Washington

Yibin Wang
Yibin Wang, PhD

University of California, Los Angeles

Program Supporters



Thursday

March 19, 2020

8:30 AM

Breakfast and Registration

9:00 AM

Introduction and Welcome Remarks

Speaker

Kari Fischer, PhD
New York Academy of Sciences
9:15 AM

Keynote Lecture ~ Branched Chain Amino Acids: A Historical Perspective

Speaker

Susan Hutson, PhD
Virginia Tech

Interest in the branched chain amino acids (BCAA), leucine, isoleucine, valine, dates back to the 1940s from the studies of Rose establishing the nutritionally essential amino acids in humans. The inborn error of BCAA catabolism, Maple Syrup Urine Disease (MSUD), was first described in the 1950s. Research on the initial enzymes in the catabolic pathway, the branched chain aminotransferases (BCATs) and the enzyme responsible for MSUD, the branched chain dehydrogenase enzyme complex (BCKDC), not only established the structures, regulation and pattern of expression of these enzymes but began to provide molecular understanding of the nonprotein functions of BCAA. In the 1970s and 80s, publications described leucine stimulation of muscle protein synthesis. selective BCAT expression in tumors, “BCAA imbalances” in diabetes and other chronic diseases. The tissue and cell specific localization of these enzymes, is responsible for shuttling of metabolites between cells and organs and their role as nitrogen donors in the body and brain, i.e., they are both nutrient signals and metabolically important. Indeed, the molecular basis for leucine effects on muscle protein synthesis and cellular immunity occur via complex pathways that were elucidated in studies on the mammalian target of rapamycin (mTOR). Emerging new molecular details and connections to other signaling pathways will determine if BCAA role in disease is causative or a consequence of the disease process.

Session 1: Fundamentals of BCAA Metabolism

10:00 AM

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.

10:30 AM

Networking Coffee Break

11:00 AM

Tracing the Metabolic Fate of Branched Chain Amino Acids in Obesity

Speaker

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

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.

11:30 AM

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

Speaker

Yibin Wang, PhD
UCLA Geffen School of Medicine

Data Blitz Presentations

12:00 PM

3 X 5 minute presentations (to be selected from submitted abstracts)

12:15 PM

Networking Lunch and Poster Session

Session 2: Translating BCAA Metabolism for Human Disease

1:45 PM

Towards Developing Specific Inhibitors for BCKD Kinase

Speaker

David Chuang, PhD
UT Southwestern

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.

2:15 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.

Coauthor: Ronald C. Wek, Indiana University School of Medicine.

2:45 PM

BCAAs and Insulin Resistance

Speaker

Zoltan Arany, PhD
University of Pennsylvania
3:15 PM

Networking Coffee Break

3:45 PM

Linking Control of BCAA Metabolism to Cardiometabolic Disease Pathogenesis

Speaker

Christopher B. Newgard, PhD
Duke University

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.

4:15 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.

4:45 PM

Closing Remarks

5:00 PM

Networking Reception and Poster Viewing

6:00 PM

Meeting Concludes