TY - JOUR
T1 - Reduced fatty acid use from cd36 deficiency deteriorates streptozotocin-induced diabetic cardiomyopathy in mice
AU - Umbarawan, Yogi
AU - Kawakami, Ryo
AU - Syamsunarno, Mas Rizky A.A.
AU - Obinata, Hideru
AU - Yamaguchi, Aiko
AU - Hanaoka, Hirofumi
AU - Hishiki, Takako
AU - Hayakawa, Noriyo
AU - Koitabashi, Norimichi
AU - Sunaga, Hiroaki
AU - Matsui, Hiroki
AU - Kurabayashi, Masahiko
AU - Iso, Tatsuya
N1 - Funding Information:
Funding: This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to M.K. (20H03671) and T.I. (17K09568), a grant from the Japan Cardiovascular Foundation and a grant from Gunma University Initiative for Advanced Research to M.K.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - CD36
KW - Ceramide
KW - Diabetic cardiomyopathy
KW - Fatty acid
KW - Glucose
KW - Metabolomics
KW - Streptozotocin
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U2 - 10.3390/metabo11120881
DO - 10.3390/metabo11120881
M3 - Article
AN - SCOPUS:85121605641
VL - 11
JO - Metabolites
JF - Metabolites
SN - 2218-1989
IS - 12
M1 - 881
ER -
