Robust suppression of cardiac energy catabolism with marked accumulation of energy substrates during lipopolysaccharide-induced cardiac dysfunction in mice

Yogi Umbarawan, Mas Rizky A.A. Syamsunarno, Hideru Obinata, Aiko Yamaguchi, Hiroaki Sunaga, Hiroki Matsui, Takako Hishiki, Tomomi Matsuura, Norimichi Koitabashi, Masaru Obokata, Hirofumi Hanaoka, Anwarul Haque, Fumio Kunimoto, Yoshito Tsushima, Makoto Suematsu, Masahiko Kurabayashi, Tatsuya Iso

研究成果: Article査読

19 被引用数 (Scopus)

抄録

Background Myocardial contractile dysfunction in sepsis has been attributed mainly to increased inflammatory cytokines, insulin resistance, and impaired oxidative phosphorylation of fatty acids (FAs). However, precise molecular mechanisms underlying the cardiac dysfunction in sepsis remain to be determined. We previously reported major shift in myocardial energy substrates from FAs to glucose, and increased hepatic ketogenesis in mice lacking fatty acid-binding protein 4 (FABP4) and FABP5 (DKO). Purpose We sought to determine whether a shift of energy substrates from FAs to glucose and increased availability of ketone bodies are beneficial or detrimental to cardiac function under the septic condition. Methods Lipopolysaccharide (LPS, 10 mg/kg) was intraperitoneally injected into wild-type (WT) and DKO mice. Twelve hours after injection, cardiac function was assessed by echocardiography and serum and hearts were collected for further analyses. Results Cardiac contractile function was more deteriorated by LPS injection in DKO mice than WT mice despite comparable changes in pro-inflammatory cytokine production. LPS injection reduced myocardial uptake of FA tracer by 30% in both types of mice, while uptake of the glucose tracer did not significantly change in either group of mice in sepsis. Storage of glycogen and triacylglycerol in hearts was remarkably increased by LPS injection in both mice. Metabolome analysis revealed that LPS-induced suppression of pool size in the TCA cycle was more enhanced in DKO hearts. A tracing study with 13C6-glucose further revealed that LPS injection substantially reduced glucose-derived metabolites in the TCA cycle and related amino acids in DKO hearts. Consistent with these findings, glucose oxidation in vitro was similarly and markedly reduced in both mice. Serum concentration of β-hydroxybutyrate and cardiac expression of genes associated with ketolysis were reduced in septic mice. Conclusions Our study demonstrated that LPS-induced cardiac contractile dysfunction is associated with the robust suppression of catabolism of energy substrates including FAs, glucose and ketone bodies and accumulation of glycogen and triacylglycerol in the heart. Thus, a fuel shift from FAs to glucose and/or ketone bodies may be detrimental rather than protective under septic conditions.

本文言語English
ページ(範囲)47-57
ページ数11
ジャーナルMetabolism: clinical and experimental
77
DOI
出版ステータスPublished - 2017 12月

ASJC Scopus subject areas

  • 内分泌学、糖尿病および代謝内科学
  • 内分泌学

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