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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Metabolites |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-1989/11/12/881 |
| _version_ | 1827671141033967616 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Yogi Umbarawan |
| collection | DOAJ |
| 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 <sup>13</sup>C<sub>6</sub>-glucose revealed that accelerated glycolysis, estimated by enrichment of <sup>13</sup>C<sub>2</sub>-citrate and <sup>13</sup>C<sub>2</sub>-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. |
| first_indexed | 2024-03-10T03:34:55Z |
| format | Article |
| id | doaj.art-1f88aced6a4e42d38998e7055f16979f |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T03:34:55Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-1f88aced6a4e42d38998e7055f16979f2023-11-23T09:32:14ZengMDPI AGMetabolites2218-19892021-12-01111288110.3390/metabo11120881Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in MiceYogi Umbarawan0Ryo Kawakami1Mas Rizky A. A. Syamsunarno2Hideru Obinata3Aiko Yamaguchi4Hirofumi Hanaoka5Takako Hishiki6Noriyo Hayakawa7Norimichi Koitabashi8Hiroaki Sunaga9Hiroki Matsui10Masahiko Kurabayashi11Tatsuya Iso12Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanEducation and Research Support Center, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Biochemistry, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo 160-8582, JapanDepartment of Biochemistry, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo 160-8582, JapanDepartment of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanDepartment of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, JapanCardiac 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 <sup>13</sup>C<sub>6</sub>-glucose revealed that accelerated glycolysis, estimated by enrichment of <sup>13</sup>C<sub>2</sub>-citrate and <sup>13</sup>C<sub>2</sub>-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.https://www.mdpi.com/2218-1989/11/12/881diabetic cardiomyopathystreptozotocinCD36glucosefatty acidceramide |
| spellingShingle | 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 Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice Metabolites diabetic cardiomyopathy streptozotocin CD36 glucose fatty acid ceramide |
| 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 | diabetic cardiomyopathy streptozotocin CD36 glucose fatty acid ceramide |
| url | https://www.mdpi.com/2218-1989/11/12/881 |
| work_keys_str_mv | AT yogiumbarawan reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT ryokawakami reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT masrizkyaasyamsunarno reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT hideruobinata reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT aikoyamaguchi reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT hirofumihanaoka reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT takakohishiki reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT noriyohayakawa reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT norimichikoitabashi reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT hiroakisunaga reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT hirokimatsui reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT masahikokurabayashi reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice AT tatsuyaiso reducedfattyacidusefromcd36deficiencydeterioratesstreptozotocininduceddiabeticcardiomyopathyinmice |