RGD Reference Report - Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis.

Authors: Ritterhoff, Julia  Young, Sara  Villet, Outi  Shao, Dan  Neto, F Carnevale  Bettcher, Lisa F  Hsu, Yun-Wei A  Kolwicz, Stephen C  Raftery, Daniel  Tian, Rong 
Citation: Ritterhoff J, etal., Circ Res. 2020 Jan 17;126(2):182-196. doi: 10.1161/CIRCRESAHA.119.315483. Epub 2019 Nov 11.
RGD ID: 329901803
Pubmed: PMID:31709908   (View Abstract at PubMed)
PMCID: PMC8448129   (View Article at PubMed Central)
DOI: DOI:10.1161/CIRCRESAHA.119.315483   (Journal Full-text)


RATIONALE: Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics.
OBJECTIVE: The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.
METHODS AND RESULTS: We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload-induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy.
CONCLUSIONS: Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypertrophic cardiomyopathy  ISOAcacb (Mus musculus)329901803; 329901803 RGD 
hypertrophic cardiomyopathy  IMP 329901803 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
mitochondrial fatty acid beta-oxidation multienzyme complex  IDA 329901803ex vivo light microscopy with digital image analysis��MMO:0000220RGD 

Objects Annotated

Genes (Rattus norvegicus)
Acacb  (acetyl-CoA carboxylase beta)
Slc2a1  (solute carrier family 2 member 1)

Genes (Mus musculus)
Acacb  (acetyl-Coenzyme A carboxylase beta)

Genes (Homo sapiens)
ACACB  (acetyl-CoA carboxylase beta)


Additional Information