Reduced fatty acid use from cd36 deficiency deteriorates streptozotocin-induced diabetic cardiomyopathy in mice

Yogi Umbarawan, Ryo Kawakami, Mas Rizky A.A. Syamsunarno, Hideru Obinata, Aiko Yamaguchi, Hirofumi Hanaoka, Takako Hishiki, Noriyo Hayakawa, Norimichi Koitabashi, Hiroaki Sunaga, Hiroki Matsui, Masahiko Kurabayashi, Tatsuya Iso

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Cardiac dysfunction is induced by multifactorial mechanisms in diabetes. Deranged fatty acid (FA) utilization, known as lipotoxicity, has long been postulated as one of the upstream events in the development of diabetic cardiomyopathy. CD36, a transmembrane glycoprotein, plays a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport with marked enhancement of glucose use. In this study, we explore whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. We found that cardiac contractile dysfunction had deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake was not reduced in CD36KO-STZ hearts, the total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. The isotopomer analysis with13 C6-glucose revealed that accelerated glycolysis, estimated by enrichment of13 C2-citrate and13 C2-malate, was markedly suppressed in CD36KO-STZ hearts. Levels of ceramides, which are cardiotoxic lipids, were not elevated in CD36KO-STZ hearts compared to wild-type-STZ ones. Furthermore, increased energy demand by transverse aortic constriction resulted in synergistic exacerbation of contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis; therefore, the limitation of FA utilization is detrimental to cardiac energetics in this model of diabetic cardiomyopathy.

Original languageEnglish
Article number881
JournalMetabolites
Volume11
Issue number12
DOIs
Publication statusPublished - 2021 Dec

Keywords

  • CD36
  • Ceramide
  • Diabetic cardiomyopathy
  • Fatty acid
  • Glucose
  • Metabolomics
  • Streptozotocin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology

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