Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts: Evidence from fatty acid-binding protein-4 and-5 knockout mice

Yogi Umbarawan, Mas Rizky A.A. Syamsunarno, Norimichi Koitabashi, Aiko Yamaguchi, Hirofumi Hanaoka, Takako Hishiki, Yoshiko Nagahata-Naito, Hideru Obinata, Motoaki Sano, Hiroaki Sunaga, Hiroki Matsui, Yoshito Tsushima, Makoto Suematsu, Masahiko Kurabayashi, Tatsuya Iso

Research output: Contribution to journalArticle

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Abstract

Aims The metabolism of the failing heart is characterized by an increase in glucose uptake with reduced fatty acid (FA) oxidation. We previously found that the genetic deletion of FA-binding protein-4 and-5 [double knockout (DKO)] induces an increased myocardial reliance on glucose with decreased FA uptake in mice. However, whether this fuel switch confers functional benefit during the hypertrophic response remains open to debate. To address this question, we investigated the contractile function and metabolic profile of DKO hearts subjected to pressure overload. Methods and results Transverse aortic constriction (TAC) significantly reduced cardiac contraction in DKO mice (DKO-TAC), although an increase in cardiac mass and interstitial fibrosis was comparable with wild-Type TAC (WT-TAC). DKO-TAC hearts exhibited enhanced glucose uptake by 8-fold compared with WT-TAC. Metabolic profiling and isotopomer analysis revealed that the pool size in the TCA cycle and the level of phosphocreatine were significantly reduced in DKO-TAC hearts, despite a marked increase in glycolytic flux. The ingestion of a diet enriched in medium-chain FAs restored cardiac contractile dysfunction in DKO-TAC hearts. The de novo synthesis of amino acids as well as FA from glycolytic flux was unlikely to be suppressed, despite a reduction in each precursor. The pentose phosphate pathway was also facilitated, which led to the increased production of a coenzyme for lipogenesis and a precursor for nucleotide synthesis. These findings suggest that reduced FA utilization is not sufficiently compensated by a robust increase in glucose uptake when the energy demand is elevated. Glucose utilization for sustained biomass synthesis further enhances diminishment of the pool size in the TCA cycle. Conclusions Our data suggest that glucose is preferentially utilized for biomass synthesis rather than ATP production during pressure-overload-induced cardiac hypertrophy and that the efficient supplementation of energy substrates may restore cardiac dysfunction caused by energy insufficiency.

Original languageEnglish
Pages (from-to)1132-1144
Number of pages13
JournalCardiovascular Research
Volume114
Issue number8
DOIs
Publication statusPublished - 2018 Jul 1

Fingerprint

Fatty Acid-Binding Proteins
Constriction
Knockout Mice
Biomass
Pressure
Glucose
Fatty Acids
Pentose Phosphate Pathway
Lipogenesis
Phosphocreatine
Metabolome
Coenzymes
Cardiomegaly
Fibrosis
Nucleotides
Eating
Adenosine Triphosphate
Diet
Amino Acids

Keywords

  • Cardiac hypertrophy
  • Energy metabolism
  • Fatty acid
  • Glucose
  • Heart failure

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts : Evidence from fatty acid-binding protein-4 and-5 knockout mice. / Umbarawan, Yogi; Syamsunarno, Mas Rizky A.A.; Koitabashi, Norimichi; Yamaguchi, Aiko; Hanaoka, Hirofumi; Hishiki, Takako; Nagahata-Naito, Yoshiko; Obinata, Hideru; Sano, Motoaki; Sunaga, Hiroaki; Matsui, Hiroki; Tsushima, Yoshito; Suematsu, Makoto; Kurabayashi, Masahiko; Iso, Tatsuya.

In: Cardiovascular Research, Vol. 114, No. 8, 01.07.2018, p. 1132-1144.

Research output: Contribution to journalArticle

Umbarawan, Y, Syamsunarno, MRAA, Koitabashi, N, Yamaguchi, A, Hanaoka, H, Hishiki, T, Nagahata-Naito, Y, Obinata, H, Sano, M, Sunaga, H, Matsui, H, Tsushima, Y, Suematsu, M, Kurabayashi, M & Iso, T 2018, 'Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts: Evidence from fatty acid-binding protein-4 and-5 knockout mice', Cardiovascular Research, vol. 114, no. 8, pp. 1132-1144. https://doi.org/10.1093/cvr/cvy063
Umbarawan, Yogi ; Syamsunarno, Mas Rizky A.A. ; Koitabashi, Norimichi ; Yamaguchi, Aiko ; Hanaoka, Hirofumi ; Hishiki, Takako ; Nagahata-Naito, Yoshiko ; Obinata, Hideru ; Sano, Motoaki ; Sunaga, Hiroaki ; Matsui, Hiroki ; Tsushima, Yoshito ; Suematsu, Makoto ; Kurabayashi, Masahiko ; Iso, Tatsuya. / Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts : Evidence from fatty acid-binding protein-4 and-5 knockout mice. In: Cardiovascular Research. 2018 ; Vol. 114, No. 8. pp. 1132-1144.
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T1 - Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts

T2 - Evidence from fatty acid-binding protein-4 and-5 knockout mice

AU - Umbarawan, Yogi

AU - Syamsunarno, Mas Rizky A.A.

AU - Koitabashi, Norimichi

AU - Yamaguchi, Aiko

AU - Hanaoka, Hirofumi

AU - Hishiki, Takako

AU - Nagahata-Naito, Yoshiko

AU - Obinata, Hideru

AU - Sano, Motoaki

AU - Sunaga, Hiroaki

AU - Matsui, Hiroki

AU - Tsushima, Yoshito

AU - Suematsu, Makoto

AU - Kurabayashi, Masahiko

AU - Iso, Tatsuya

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N2 - Aims The metabolism of the failing heart is characterized by an increase in glucose uptake with reduced fatty acid (FA) oxidation. We previously found that the genetic deletion of FA-binding protein-4 and-5 [double knockout (DKO)] induces an increased myocardial reliance on glucose with decreased FA uptake in mice. However, whether this fuel switch confers functional benefit during the hypertrophic response remains open to debate. To address this question, we investigated the contractile function and metabolic profile of DKO hearts subjected to pressure overload. Methods and results Transverse aortic constriction (TAC) significantly reduced cardiac contraction in DKO mice (DKO-TAC), although an increase in cardiac mass and interstitial fibrosis was comparable with wild-Type TAC (WT-TAC). DKO-TAC hearts exhibited enhanced glucose uptake by 8-fold compared with WT-TAC. Metabolic profiling and isotopomer analysis revealed that the pool size in the TCA cycle and the level of phosphocreatine were significantly reduced in DKO-TAC hearts, despite a marked increase in glycolytic flux. The ingestion of a diet enriched in medium-chain FAs restored cardiac contractile dysfunction in DKO-TAC hearts. The de novo synthesis of amino acids as well as FA from glycolytic flux was unlikely to be suppressed, despite a reduction in each precursor. The pentose phosphate pathway was also facilitated, which led to the increased production of a coenzyme for lipogenesis and a precursor for nucleotide synthesis. These findings suggest that reduced FA utilization is not sufficiently compensated by a robust increase in glucose uptake when the energy demand is elevated. Glucose utilization for sustained biomass synthesis further enhances diminishment of the pool size in the TCA cycle. Conclusions Our data suggest that glucose is preferentially utilized for biomass synthesis rather than ATP production during pressure-overload-induced cardiac hypertrophy and that the efficient supplementation of energy substrates may restore cardiac dysfunction caused by energy insufficiency.

AB - Aims The metabolism of the failing heart is characterized by an increase in glucose uptake with reduced fatty acid (FA) oxidation. We previously found that the genetic deletion of FA-binding protein-4 and-5 [double knockout (DKO)] induces an increased myocardial reliance on glucose with decreased FA uptake in mice. However, whether this fuel switch confers functional benefit during the hypertrophic response remains open to debate. To address this question, we investigated the contractile function and metabolic profile of DKO hearts subjected to pressure overload. Methods and results Transverse aortic constriction (TAC) significantly reduced cardiac contraction in DKO mice (DKO-TAC), although an increase in cardiac mass and interstitial fibrosis was comparable with wild-Type TAC (WT-TAC). DKO-TAC hearts exhibited enhanced glucose uptake by 8-fold compared with WT-TAC. Metabolic profiling and isotopomer analysis revealed that the pool size in the TCA cycle and the level of phosphocreatine were significantly reduced in DKO-TAC hearts, despite a marked increase in glycolytic flux. The ingestion of a diet enriched in medium-chain FAs restored cardiac contractile dysfunction in DKO-TAC hearts. The de novo synthesis of amino acids as well as FA from glycolytic flux was unlikely to be suppressed, despite a reduction in each precursor. The pentose phosphate pathway was also facilitated, which led to the increased production of a coenzyme for lipogenesis and a precursor for nucleotide synthesis. These findings suggest that reduced FA utilization is not sufficiently compensated by a robust increase in glucose uptake when the energy demand is elevated. Glucose utilization for sustained biomass synthesis further enhances diminishment of the pool size in the TCA cycle. Conclusions Our data suggest that glucose is preferentially utilized for biomass synthesis rather than ATP production during pressure-overload-induced cardiac hypertrophy and that the efficient supplementation of energy substrates may restore cardiac dysfunction caused by energy insufficiency.

KW - Cardiac hypertrophy

KW - Energy metabolism

KW - Fatty acid

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KW - Heart failure

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