Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
_version_ 1784622329944342528
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
work_keys_str_mv AT umbarawanyogi reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT kawakamiryo reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT syamsunarnomasrizkyaa reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT obinatahideru reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT yamaguchiaiko reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT hanaokahirofumi reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT hishikitakako reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT hayakawanoriyo reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT koitabashinorimichi reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT sunagahiroaki reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT matsuihiroki reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT kurabayashimasahiko reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice
AT isotatsuya reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice