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Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice
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 upt...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707002/ https://www.ncbi.nlm.nih.gov/pubmed/34940639 http://dx.doi.org/10.3390/metabo11120881 |
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author | Umbarawan, Yogi Kawakami, Ryo Syamsunarno, Mas Rizky A. A. Obinata, Hideru Yamaguchi, Aiko Hanaoka, Hirofumi Hishiki, Takako Hayakawa, Noriyo Koitabashi, Norimichi Sunaga, Hiroaki Matsui, Hiroki Kurabayashi, Masahiko Iso, Tatsuya |
author_facet | Umbarawan, Yogi Kawakami, Ryo Syamsunarno, Mas Rizky A. A. Obinata, Hideru Yamaguchi, Aiko Hanaoka, Hirofumi Hishiki, Takako Hayakawa, Noriyo Koitabashi, Norimichi Sunaga, Hiroaki Matsui, Hiroki Kurabayashi, Masahiko Iso, Tatsuya |
author_sort | Umbarawan, Yogi |
collection | PubMed |
description | 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 with (13)C(6)-glucose revealed that accelerated glycolysis, estimated by enrichment of (13)C(2)-citrate and (13)C(2)-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. |
format | Online Article Text |
id | pubmed-8707002 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87070022021-12-25 Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice Umbarawan, Yogi Kawakami, Ryo Syamsunarno, Mas Rizky A. A. Obinata, Hideru Yamaguchi, Aiko Hanaoka, Hirofumi Hishiki, Takako Hayakawa, Noriyo Koitabashi, Norimichi Sunaga, Hiroaki Matsui, Hiroki Kurabayashi, Masahiko Iso, Tatsuya Metabolites Article 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 with (13)C(6)-glucose revealed that accelerated glycolysis, estimated by enrichment of (13)C(2)-citrate and (13)C(2)-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. MDPI 2021-12-17 /pmc/articles/PMC8707002/ /pubmed/34940639 http://dx.doi.org/10.3390/metabo11120881 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Umbarawan, Yogi Kawakami, Ryo Syamsunarno, Mas Rizky A. A. Obinata, Hideru Yamaguchi, Aiko Hanaoka, Hirofumi Hishiki, Takako Hayakawa, Noriyo Koitabashi, Norimichi Sunaga, Hiroaki Matsui, Hiroki Kurabayashi, Masahiko Iso, Tatsuya Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice |
title | Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice |
title_full | Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice |
title_fullStr | Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice |
title_full_unstemmed | Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice |
title_short | Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice |
title_sort | reduced fatty acid use from cd36 deficiency deteriorates streptozotocin-induced diabetic cardiomyopathy in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707002/ https://www.ncbi.nlm.nih.gov/pubmed/34940639 http://dx.doi.org/10.3390/metabo11120881 |
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