Kazuhiro Nakatani1, Tadashi Watabe2, Daisaku Masuda1, Masao Imaizumi3, Eku Shimosegawa4, Takuya Kobayashi1, Masami Sairyo1, Yinghong Zhu1, Takeshi Okada1, Ryota Kawase1, Hajime Nakaoka1, Atsuhiko Naito5, Tohru Ohama6, Masahiro Koseki1, Toru Oka1, Hiroshi Akazawa5, Makoto Nishida6, Issei Komuro7, Yasushi Sakata1, Jun Hatazawa4, Shizuya Yamashita8. 1. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. 2. Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. 3. Hanwa Intelligent Medical Center, 3176 Fukai-kitamachi, Nakaku, Sakai, Osaka 599-8271, Japan. 4. Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. 5. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongou, Bunkyo-ku, Tokyo 113-8655, Japan. 6. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Health Care Center, Osaka University, 1-7 Machikaneyama, Toyonaka, Osaka 560-0043, Japan. 7. Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongou, Bunkyo-ku, Tokyo 113-8655, Japan. 8. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Community Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Abstract
AIMS: CD36 is an important transporter of long-chain fatty acids (LCFAs) in the myocardium. As we have reported previously, CD36-deficient patients demonstrate a marked reduction in myocardial uptake of (123)I-15-(p-iodophenyl)-(R, S)-methyl pentadecanoic acid (BMIPP), which is an analog of LCFAs, while myocardial (18)F-fluorodeoxy-glucose (FDG) uptake is increased. However, it has not been clarified whether energy provision is preserved in patients with CD36 deficiency. The aims of the current study were to investigate the myocardial uptake of glucose and alterations in myocardial metabolites in wild-type (WT) and CD36 knockout (KO) mice. METHODS AND RESULTS: High-resolution positron emission tomography (PET) demonstrated markedly enhanced glucose uptake in KO mouse hearts compared with those of WT mice in real-time. The myocardial protein expression of glucose transporter protein 1 (GLUT1) was significantly enhanced in KO mice compared to WT mice, whereas that of GLUT4 was not altered. While the myocardial expression of genes involved in fatty acid metabolism did not increase in KO mice, that of genes related to glucose utilization compensatorily increased in KO mice. The metabolomic analysis of cardiac tissues revealed that the myocardial concentrations of ATP and phosphocreatine were maintained, even in KO mice. The concentration of 3-hydroxybutyric acid and mRNA expression of hydroxybutyrate dehydrogenase in the heart were significantly higher in KO than in WT mice. CONCLUSION: These data suggest that high-energy phosphate might be preserved by the increased utilization of glucose and ketone bodies in CD36KO mouse hearts under conditions of deficient LCFA uptake.
AIMS: CD36 is an important transporter of long-chain fatty acids (LCFAs) in the myocardium. As we have reported previously, CD36-deficientpatients demonstrate a marked reduction in myocardial uptake of (123)I-15-(p-iodophenyl)-(R, S)-methyl pentadecanoic acid (BMIPP), which is an analog of LCFAs, while myocardial (18)F-fluorodeoxy-glucose (FDG) uptake is increased. However, it has not been clarified whether energy provision is preserved in patients with CD36 deficiency. The aims of the current study were to investigate the myocardial uptake of glucose and alterations in myocardial metabolites in wild-type (WT) and CD36 knockout (KO) mice. METHODS AND RESULTS: High-resolution positron emission tomography (PET) demonstrated markedly enhanced glucose uptake in KO mouse hearts compared with those of WT mice in real-time. The myocardial protein expression of glucose transporter protein 1 (GLUT1) was significantly enhanced in KO mice compared to WT mice, whereas that of GLUT4 was not altered. While the myocardial expression of genes involved in fatty acid metabolism did not increase in KO mice, that of genes related to glucose utilization compensatorily increased in KO mice. The metabolomic analysis of cardiac tissues revealed that the myocardial concentrations of ATP and phosphocreatine were maintained, even in KO mice. The concentration of 3-hydroxybutyric acid and mRNA expression of hydroxybutyrate dehydrogenase in the heart were significantly higher in KO than in WT mice. CONCLUSION: These data suggest that high-energy phosphate might be preserved by the increased utilization of glucose and ketone bodies in CD36KO mouse hearts under conditions of deficient LCFA uptake.
Authors: Tijs Vandoorne; Stefan De Smet; Monique Ramaekers; Ruud Van Thienen; Katrien De Bock; Kieran Clarke; Peter Hespel Journal: Front Physiol Date: 2017-05-23 Impact factor: 4.566