Kazuhiro Nomura, Shinichi Kinoshita, Nao Mizusaki, Yoko Senga, Tsutomu Sasaki, Tadahiro Kitamura, Hiroshi Sakaue, Aki Emi, Tetsuya Hosooka, Masahiro Matsuo, Hitoshi Okamura, Taku Amo, M Alexander Wolf, Naomi Kamimura, Shigeo Ohta, Tomoo Itoh, Yoshitake Hayashi, Hiroshi Kiyonari, Anna Krook, R Juleen Zierath, Masato Kasuga and Wataru Ogawa : Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism., Molecular Metabolism, Vol.86, 101968, 2024.
(Summary)
The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.
Kazuhiro Nomura, Satoshi Inagaki, Naokazu Muramae, Hiroaki Takahashi, Kozue Abe, Kenji Kato, Yoshiaki Kido and Tomokazu Matsuda : Association of short-term changes in HbA1c with body composition and the importance of muscle maintenance in patients with Type 2 diabetes., Journal of Diabetes and its Complications, Vol.38, No.6, 108746, 2024.
(Summary)
This study shows a limited association between short-term changes in glucose metabolism and changes in body composition in patients with type 2 diabetes. Therefore, interventions aimed at reducing adiposity may not affect glucose metabolism in the short term, while interventions focused on maintaining or enhancing muscle mass and bone mineral content may play an important role in diabetes management.
(Keyword)
Diabetes Mellitus, Type 2 / Glycated Hemoglobin / Body Composition / Muscle, Skeletal / Bone Density / Body Mass Index
Hiromi Matsuo, Ryota Matsui, Koshi Kumagai, Satoshi Ida, Yoko Saino, Aya Fujihara, Kumi Takagi, Yukiko Itami, Misuzu Ishii, Naoki Moriya, Yuna Izumi-Mishima, Kazuhiro Nomura, M Yasuo Tsutsumi, Souya Nunobe, Rie Tsutsumi and Hiroshi Sakaue : Impact of Olfactory Change on Postoperative Body Weight Loss in Patients with Gastric Cancer after Gastrectomy., Nutrients, Vol.16, No.6, 851, 2024.
(Summary)
= 0.048). In conclusion, olfactory changes emerged as an independent risk factor for postoperative weight loss at one month in patients with gastric cancer following gastrectomy.
Yu Hirata, Kazuhiro Nomura, Daisuke Kato, Yoshihisa Tachibana, Takahiro Niikura, Kana Uchiyama, Tetsuya Hosooka, Tomoaki Fukui, Keisuke Oe, Ryosuke Kuroda, Yuji Hara, Takahiro Adachi, Koji Shibasaki, Hiroaki Wake and Wataru Ogawa : A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy., The Journal of Clinical Investigation, Vol.132, No.10, 1-13, 2022.
(Summary)
Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Krüppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the cytosolic Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.
Naoki Kuramoto, Kazuhiro Nomura, Daisuke Kohno, Tadahiro Kitamura, Gerard Karsenty, Tetsuya Hosooka and Wataru Ogawa : Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load., Scientific Reports, Vol.11, No.1, 3447, 2021.
(Summary)
Phosphatidylinositol 3-kinase (PI3K) plays an important role in protein metabolism and cell growth. We here show that mice (M-PDK1KO mice) with skeletal muscle-specific deficiency of 3'-phosphoinositide-dependent kinase 1 (PDK1), a key component of PI3K signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of mechanical load-induced muscle hypertrophy. Whereas mechanical load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by mechanical load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of kinase cascades such as the S6K-S6 axis, which plays a key role in protein synthesis. Administration of the β2-adrenergic receptor (AR) agonist clenbuterol activated the S6K-S6 axis in skeletal muscle and induced muscle hypertrophy in mice. These effects of clenbuterol were attenuated in M-PDK1KO mice, and mechanical load-induced activation of the S6K-S6 axis and muscle hypertrophy were inhibited in mice with skeletal muscle-specific deficiency of β2-AR. Our results suggest that PDK1 regulates skeletal muscle mass under the static condition and that it contributes to mechanical load-induced muscle hypertrophy, at least in part by mediating signaling from β2-AR.
Nao Mizusaki, Kazuhiro Nomura, Tetsuya Hosooka, Masashi Shiomi, Kazuo Ogawa, Tetsuto Tsunoda, Yoshikazu Tamori and Wataru Ogawa : The Novel Lipid-Lowering Drug D-47 Ameliorates Hepatic Steatosis and Promotes Brown/Beige-Like Change of White Adipose Tissue in db/db Mice., The Kobe Journal of Medical Sciences, Vol.65, No.1, E36-E43, 2019.
(Summary)
D-47 is a newly developed solid dispersion of the arginine salt of (S)-(+)-4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidin-4-yl]methoxybenzoic acid (S-2E), which inhibits sterol and fatty acid synthesis. D-47 was recently shown to lower the serum level and hepatic content of both triglyceride and cholesterol in a rabbit model of familial hypercholesterolemia. We here investigated the effects of D-47 on dyslipidemia and hepatic steatosis in comparison with those of bezafibrate in the db/db mouse model of obesity. Treatment of db/db mice with D-47 or bezafibrate for 14 days lowered the serum triglyceride concentration without affecting that of cholesterol. D-47, but not bezafibrate, almost completely eliminated lipid droplets in hepatocytes and markedly lowered the triglyceride content of the liver in these mice. The two agents induced similar changes in the hepatic expression of genes including those related to β-oxidation or fatty acid synthesis. D-47 however significantly reduced the mass of white adipose tissue and up-regulated the expression of genes related to energy expenditure, mitochondrial function, fatty acid oxidation or lipolysis in this tissue, indicating that D-47 induced the brown/beige adipocyte-like change in white adipose tissue, whereas bezafibrate had no such effects. Treatment of 3T3-L1 adipocytes with D-47 provoked the expression of genes related to mitochondrial function, fatty acid oxidation or lipolysis. Our data have thus shown that D-47 ameliorated hypertriglyceridemia and hepatic steatosis in an animal model of obesity, and they suggest that this latter effect might be mediated through the change of adipose tissue characteristics.
Diabetes mellitus is associated with various disorders of the locomotor system including the decline in mass and function of skeletal muscle. The mechanism underlying this association has remained ambiguous, however. We now show that the abundance of the transcription factor KLF15 as well as the expression of genes related to muscle atrophy are increased in skeletal muscle of diabetic model mice, and that mice with muscle-specific KLF15 deficiency are protected from the diabetes-induced decline of skeletal muscle mass. Hyperglycemia was found to upregulate the KLF15 protein in skeletal muscle of diabetic animals, which is achieved via downregulation of the E3 ubiquitin ligase WWP1 and consequent suppression of the ubiquitin-dependent degradation of KLF15. Our results revealed that hyperglycemia, a central disorder in diabetes, promotes muscle atrophy via a WWP1/KLF15 pathway. This pathway may serve as a therapeutic target for decline in skeletal muscle mass accompanied by diabetes mellitus.
Kenji Sugawara, Kazuhiro Nomura, Yuko Okada, Aki Sugano, Masaaki Matsumoto, Toru Takarada, Atsuko Takeuchi, Hiroyuki Awano, Yushi Hirota, Hisahide Nishio, Yutaka Takaoka and Wataru Ogawa : In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4α identified in maturity-onset diabetes of the young type 1., Journal of Diabetes Investigation, Vol.10, No.3, 680-684, 2018.
(Summary)
Mutations of the hepatocyte nuclear factor 4α (HNF4α) gene give rise to maturity-onset diabetes of the young type 1. Although many such mutations have been identified in affected individuals, part of these mutations has been characterized with regard to their pathological relevance. We here identified a missense mutation (c.773G>A, p.R258H) of HNF4A in a mother and daughter with early-onset diabetes and impaired insulin secretion. In silico simulation and in vitro luciferase reporter analyses showed that the mutation impairs the stability of self-dimerization and the transactivation activity of HNF4α. Although arginine-258 does not appear to participate directly in dimerization, its mutation alters the electrostatic surface potential of the dimer interface. Our results thus suggest that this mutation impairs the function of HNF4α and thereby contributes to the pathogenesis of maturity-onset diabetes of the young type 1.
Kaku Matsugi, Tetsuya Hosooka, Kazuhiro Nomura and Wataru Ogawa : Thrombospondin 1 Suppresses Insulin Signaling in C2C12 Myotubes., The Kobe Journal of Medical Sciences, Vol.62, No.1, E13-8, 2016.
(Summary)
Thrombospondin 1 (TSP-1) is abundantly expressed in visceral adipose tissue and this expression is up-regulated in obese humans and rodents. Recent studies showed that genetic deletion of TSP-1 protects mice from diet-induced insulin resistance. However, the molecular mechanism is largely unknown. In this study, we examined the effect of recombinant TSP-1 on insulin signaling in cultured cells from insulin sensitive tissues to investigate whether TSP-1 could act as an adipokine. Here we show that treatment with recombinant TSP-1 suppressed insulin signaling in cultured muscle cells, which was accompanied by the activation of stress signaling such as JNK, p38, and IKK. These results suggest that TSP-1 acts as an adipokine which is involved in the pathogenesis of obesity-induced insulin resistance. Thus, TSP-1 could be a potential target for the treatment of insulin resistance and metabolic disease related to insulin resistance.
(Keyword)
Adipokines / Animals / Cell Line / Hep G2 Cells / Humans / Insulin / Insulin Resistance / MAP Kinase Signaling System / Male / Mice / Mice, Inbred C57BL / Muscle Fibers, Skeletal / Recombinant Proteins / Signal Transduction / Thrombospondin 1
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● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27492207
Yukiko Kawasaki-Ogita, Yoshiyuki Hamamoto, Sachiko Honjo, Hiroki Ikeda, Yoshiharu Wada, Kazuhiro Nomura, Yorihiro Iwasaki, Ryuji Nohara and Hiroyuki Koshiyama : The limited usefulness of the treadmill test or a risk-guided approach in screening for asymptomatic coronary heart disease in Japanese patients with type 2 diabetes., Internal Medicine, Vol.51, No.24, 3337-3342, 2012.
(Summary)
Neither the TTT as a first-line test nor the ADA guidelines are sufficiently adequate screening methods to detect asymptomatic CHD in Japanese subjects with type 2 diabetes. Conducting routine screening for asymptomatic CHD in Japanese patients with type 2 diabetes may therefore not be very useful.
(Keyword)
Asian People / Asymptomatic Diseases / Coronary Disease / Diabetes Mellitus, Type 2 / Diabetic Angiopathies / Exercise Test / Female / Humans / Male / Middle Aged / Myocardial Perfusion Imaging / Prospective Studies / Reproducibility of Results / Risk Assessment
Kazuhiro Nomura, Hiroki Ikeda, Kanako Mori, Yoshiyuki Hamamoto, Sachiko Honjo, Yukiko Kawasaki, Yoshiharu Wada and Hiroyuki Koshiyama : Less variation of R-R interval of electrocardiogram in nonobese type 2 diabetes with nocturnal intermittent hypoxia., Endocrine Journal, Vol.60, No.2, 225-230, 2012.
(Summary)
Obesity is a major risk factor for sleep-disordered breathing (SDB). However, many Japanese subjects with diabetes are less obese despite compared with Caucasian. We evaluated the relationship between SDB and clinical characteristics other than obesity, especially in relation to cardiac autonomic neuropathy (CAN) in Japanese subjects with diabetes. The study included a total of 261 consecutive Japanese subjects with type 2 diabetes, including nonobese subjects defined as BMI <25 kg/m² for Japanese. SDB was screened by 4% oxygen desaturation index (ODI) level of 5 or more events per hour, which was measured by nocturnal pulse oximetry. CAN was examined with the variation of R-R intervals (CVRR). The SDB were found in 24.5% of total subjects and 16.3% of nonobese subjects with type 2 diabetes, respectively. The nonobese type 2 diabetes subjects with SDB had significantly lower coefficient of CVRR than those without SDB. Multiple regression analysis revealed that BMI and heart rate were significant independent factors for SDB in total subjects with type 2 diabetes, but CVRR was the only significant independent factor for SDB in nonobese subjects with type 2 diabetes. These findings suggest that the presence of SDB should be kept in mind in type 2 diabetic patients with abnormality in CVRR variation in electrocardiogram even though they are not obese.
(Keyword)
Aged / Arrhythmias, Cardiac / Autonomic Nervous System Diseases / Blood Gas Monitoring, Transcutaneous / Body Mass Index / Diabetes Mellitus, Type 2 / Diabetic Neuropathies / Electrocardiography / Female / Heart / Heart Rate / Humans / Japan / Male / Middle Aged / Overweight / Prevalence / Risk Factors / Sleep Apnea Syndromes
Yoshiyuki Hamamoto, Sachiko Honjo, Yukiko Kawasaki, Hiroki Ikeda, Kanako Mori, Kanta Fujimoto, Hisato Tatsuoka, Yorihiro Iwasaki, Kazuhiro Nomura, Yoshiharu Wada and Hiroki Koshiyama : Relationship between telmisartan dose and glycaemic control in Japanese patients with type 2 diabetes mellitus and hypertension: a retrospective study., Clinical Drug Investigation, Vol.32, No.9, 577-582, 2012.
(Summary)
Our results suggest that telmisartan influences glycaemic control in a dose-dependent manner; doses 40 mg/day may be needed to improve glycaemic control. Our data also suggest that patients with higher baseline HbA(1c) may experience greater improvements in glycaemic control with telmisartan.
(Keyword)
Angiotensin II Type 1 Receptor Blockers / Benzimidazoles / Benzoates / Blood Glucose / Diabetes Mellitus, Type 2 / Dose-Response Relationship, Drug / Female / Humans / Hypertension / Japan / Male / Middle Aged / Retrospective Studies / Telmisartan
Tomohisa Aoyama, Hiroki Ikeda, Yoshiyuki Hamamoto, Sachiko Honjo, Kazuhiro Nomura, Yoshiharu Wada, Jun Fujikawa, Yasuaki Hayashino, Shunichi Fukuhara and Hiroyuki Koshiyama : Clinical heterogeneity of adult Japanese diabetes depending on titers of glutamic acid decarboxylase autoantibodies., Journal of Diabetes Investigation, Vol.3, No.3, 266-270, 2012.
(Summary)
Aims/Introduction: We examined whether levels of glutamic acid decarboxylase autoantibodies (GADAb) might show the clinical heterogeneity of adult Japanese diabetes. In this cross-sectional study, the serum levels of GADAb were measured in a total of 1857 consecutive adult diabetic patients aged 20 years or older. The patients with positive GADAb, arbitrarily defined as ≥1.5 U/mL, were divided into quartiles according to the number of patients. The age- and sex-matched diabetic patients without GADAb were selected as a control group. A total of 103 (5.5%) of the diabetic patients had GADAb, and showed higher HbA1c and serum high-density lipoprotein (HDL) cholesterol levels, lower body mass index (BMI), urinary C-peptide immunoreactivity (CPR), serum triglycerides (TG) and uric acid (UA) levels, and lower prevalence of metabolic syndrome than the control group (P < 0.05). Quartiles 3 and 4 (i.e. GADAb ≥4.6 U/mL) showed a higher HbA1c level, lower BMI, urinary CPR, serum TG and UA levels, quartile 2 (2.5 ≤ GADAb < 4.6 U/mL) showed a lower BMI level than the control group (P < 0.05). Among the clinical parameters, we observed significant upward trends for both HbA1c and serum HDL cholesterol levels, and significant downward trends for BMI, serum TG and UA, urinary CPR levels, and prevalence of metabolic syndrome across GADAb quartiles (P < 0.05 for trend). These results show that the clinical phenotype of adult Japanese diabetes correlates with GADAb levels, and that patients with GADAb (≥2.5 U/mL) show different characteristics from those without GADAb, although further longitudinal studies are required. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00190.x, 2011).
Shuying Li, Wataru Ogawa, Aki Emi, Kumiko Hayashi, Yoko Senga, Kazuhiro Nomura, Kenta Hara, Demin Yu and Masato Kasuga : Role of S6K1 in regulation of SREBP1c expression in the liver., Biochemical and Biophysical Research Communications, Vol.412, No.2, 197-202, 2011.
(Summary)
The transcription factor sterol regulatory element-binding protein 1c (SREBP1c) plays an important role in the control of fatty acid metabolism in the liver. Evidence suggests that mammalian target of rapamycin (mTOR) complex 1 (mTORC1) contributes to the regulation of SREBP1c expression, but signaling downstream of mTORC1 remains unclear. We have now shown that medium rich in branched-chain amino acids stimulates expression of the SREBP1c gene in cultured hepatocytes in a manner sensitive both to rapamycin, a pharmacological inhibitor of mTORC1, and to a short hairpin RNA (shRNA) specific for S6 kinase 1 (S6K1), a downstream effector of mTORC1. The phosphorylation of S6K1 was increased in the liver of obese db/db mice. Furthermore, depletion of hepatic S6K1 in db/db mice with the use of an adenovirus vector encoding S6K1 shRNA resulted in down-regulation of SREBP1c gene expression in the liver as well as a reduced hepatic triglyceride content and serum triglyceride concentration. These results thus suggest that S6K1 regulates SREBP1c expression both in cultured hepatocytes and in mouse liver, and that increased hepatic activity of S6K1 contributes at least in part to the pathogenesis of obesity-induced hepatic steatosis and hypertriglyceridemia.
(Keyword)
Animals / Cell Line / Chromones / Fatty Liver / Gene Expression Regulation / Hepatocytes / Hypertriglyceridemia / Liver / Mechanistic Target of Rapamycin Complex 1 / Mice / Mice, Inbred Strains / Morpholines / Multiprotein Complexes / Obesity / Proteins / RNA, Small Interfering / Ribosomal Protein S6 Kinases, 90-kDa / Sirolimus / Sterol Regulatory Element Binding Protein 1 / TOR Serine-Threonine Kinases
Kazuhiro Nomura, Yoshiyuki Hamamoto, Shiho Takahara, Osamu Kikuchi, Sachiko Honjo, Hiroki Ikeda, Yoshiharu Wada, Koichro Nabe, Ryosuke Okumra and Hiroyuki Koshiyama : Relationship between carotid intima-media thickness and silent cerebral infarction in Japanese subjects with type 2 diabetes., Diabetes Care, Vol.33, No.1, 168-170, 2009.
(Summary)
We examined the relationship between intima-media thickness of common carotid artery (CCA-IMT) and silent cerebral infarction (SCI) with the magnetic resonance imaging (MRI) study in Japanese subjects with type 2 diabetes. The brain MRI study and the carotid ultrasonography were performed in a total of 217 consecutive Japanese subjects with type 2 diabetes. Various risk factors for SCI were examined using multiple logistic analyses. The SCI was found in 60.4% of the diabetic subjects. In the diabetic subjects, age, systolic blood pressure (SBP), pulse wave velocity, and CCA-IMT were significantly higher in the subjects with SCI than in those without it. Multiple logistic analyses indicated that age, SBP, and CCA-IMT were significant and independent risk factors of SCI in the diabetic subjects. CCA-IMT, but not pulse wave velocity, was independently associated with SCI in Japanese subjects with type 2 diabetes.
(Keyword)
Aged / Asian People / Cerebral Infarction / Diabetes Mellitus, Type 2 / Female / Humans / Magnetic Resonance Imaging / Male / Middle Aged / Risk Factors / Tunica Intima / Tunica Media / Ultrasonography
Tetsuya Kimura, Hiroki Ikeda, Jun Fujikawa, Kazuhiro Nomura, Tomohisa Aoyama, Yoshiharu Wada, Koichiro Nabe, Yoshiyuki Hamamoto, Sachiko Honjo and Hiroyuki Koshiyama : Usefulness of serum cystatin C in Japanese patients with type 2 diabetes mellitus and nephropathy., Diabetes Research and Clinical Practice, Vol.83, No.2, e58-61, 2008.
(Summary)
We examined usefulness of serum cystatin C to detect chronic kidney disease (CKD) stage >or=3, which was defined by Modification of Diet in Renal Disease formula. Serum cystatin C could detect CKD stage >or=3 with high efficacy in 289 Japanese patients with type 2 diabetes and nephropathy.
(Keyword)
Adult / Aged / Aged, 80 and over / Cross-Sectional Studies / Cystatin C / Diabetes Mellitus, Type 2 / Diabetic Nephropathies / Disease Progression / Female / Glomerular Filtration Rate / Humans / Kidney Failure, Chronic / Male / Middle Aged / Predictive Value of Tests / ROC Curve / Sensitivity and Specificity
Yasuyuki Arai, Koichiro Nabe, Hiroki Ikeda, Sachiko Honjo, Yoshiharu Wada, Yoshiyuki Hamamoto, Kazuhiro Nomura, Tomokazu Aoki, Toshiaki Sano and Hiroyuki Koshiyama : A case of lymphocytic panhypophysitis (LPH) during pregnancy., Endocrine, Vol.32, No.1, 117-121, 2007.
(Summary)
A 37-year-old pregnant woman developed continuous headache in the 10th week of pregnancy, followed by bilateral visual field defect and general malaise in the 24th week. The brain magnetic resonance imaging showed a pituitary mass. In laboratory examination, plasma concentration of free thyroxine, thyroid stimulating hormone (TSH), cortisol, and adrenocorticotropic hormone (ACTH) was low. General malaise vanished shortly after the replacement therapy of glucocorticoid and thyroid hormone, but partial central diabetes insipidus (CDI) appeared, which could be treated with desmopressin acetate (DDAVP). The visual field defect having enlarged, transsphenoidal surgery was performed in the 31st week of pregnancy. Adenohypophysis could be resected, and it showed infiltration of mature lymphocytes. After the surgery, the visual defect had improved, but hormone replacement was still necessary. She delivered a baby in the 38th week without any trouble. Provocative tests after delivery revealed a low response in TSH, prolactin (PRL), and follicle stimulating hormone (FSH). Hormone replacement and DDAVP administration was necessary in the same doses after delivery. The diagnosis was lymphocytic panhypophysitis (LPH). In the case of pregnant woman, LPH should be included in the differential diagnosis of pituitary mass for the fetomaternal safety.
Kazuhiro Nomura, Hoshimi Kanemura, Takaya Satoh and Tohru Kataoka : Identification of a novel domain of Ras and Rap1 that directs their differential subcellular localizations., The Journal of Biological Chemistry, Vol.279, No.21, 22664-22673, 2004.
(Summary)
The small GTPase Ha-Ras and Rap1A exhibit high mutual sequence homology and share various target proteins. However, they exert distinct biological functions and exhibit differential subcellular localizations; Rap1A is predominantly localized in the perinuclear region including the Golgi apparatus and endosomes, whereas Ha-Ras is predominantly localized in the plasma membrane. Here, we have identified a small region in Rap1A that is crucial for its perinuclear localization. Analysis of a series of Ha-Ras-Rap1A chimeras shows that Ha-Ras carrying a replacement of amino acids 46-101 with that of Rap1 exhibits the perinuclear localization. Subsequent mutational studies indicate that Rap1A-type substitutions within five amino acids at positions 85-89 of Ha-Ras, such as NNTKS85-89TAQST, NN85-86TA, and TKS87-89QST, are sufficient to induce the perinuclear localization of Ha-Ras. In contrast, substitutions of residues surrounding this region, such as FAI82-84YSI and FEDI90-93FNDL, have no effect on the plasma membrane localization of Ha-Ras. A chimeric construct consisting of amino acids 1-134 of Rap1A and 134-189 of Ha-Ras, which harbors both the palmitoylation and farnesylation sites of Ha-Ras, exhibits the perinuclear localization like Rap1A. Introduction of a Ha-Ras-type substitution into amino acids 85-89 (TAQST85-89NNTKS) of this chimeric construct causes alteration of its predominant subcellular localization site from the perinuclear region to the plasma membrane. These results indicate that a previously uncharacterized domain spanning amino acids 85-89 of Rap1A plays a pivotal role in its perinuclear localization. Moreover, this domain acts dominantly over COOH-terminal lipid modification of Ha-Ras, which has been considered to be essential and sufficient for the plasma membrane localization.
Hirotaka Imai, Tomoko Koumura, Ryo Nakajima, Kazuhiro Nomura and Yasuhito Nakagawa : Protection from inactivation of the adenine nucleotide translocator during hypoglycaemia-induced apoptosis by mitochondrial phospholipid hydroperoxide glutathione peroxidase., The Biochemical journal, Vol.371, No.Pt 3, 799-809, 2003.
(Summary)
We demonstrated that mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx) first suppressed the dissociation of cytochrome c (cyt c) from cardiolipin (CL) in mitochondrial inner membranes and then apoptosis caused by the hypoglycaemia by the prevention of peroxidation of CL [Nomura, Imai, Koumura, Arai and Nakagawa (1999) J. Biol. Chem. 274, 29294-29302; Nomura, Imai, Koumura, Kobayashi and Nakagawa (2000) Biochem. J. 351, 183-193]. The present study shows the involvement of peroxidation of CL in the inactivation of adenine nucleotide translocator (ANT) and the opening of permeability transition pores by using the system of ANT-reconstituted liposome and isolated mitochondria. ANT activity appeared in dioleoyl phosphatidylcholine proteoliposome containing 10% (mol/mol) CL or phosphatidylglycerol (PG), but not other classes of phospholipids. ANT activity was competitively inhibited by the addition of cardiolipin hydroperoxide (CLOOH) in reconstituted liposomes containing CL. However, phosphatidylcholine hydroperoxide failed to inactivate the activity of ANT. The activity of ANT in reconstituted liposomes, including CLOOH, recovered when CLOOH in reconstituted liposome was reduced to hydroxycardiolipin by incubation with PHGPx. The activity of ANT was determined in rat basophil leukaemia RBL2H3 cells after their exposure to 2-deoxyglucose. ANT activity decreased to 50% of the control level by 4 h in response to apoptosis. In parallel, cyt c and apoptosis-inducing factor (AIF) were released from mitochondria. Suppression of the accumulation of CLOOH by overexpression of PHGPx in mitochondria effectively prevented the inactivation of ANT, the opening of permeability transition pores and the release of cyt c and AIF from mitochondria in hypoglycaemia-induced apoptotic cells. These findings suggest that mitochondrial PHGPx might be involved in the modulation of the activity of ANT and the opening of pores for the release of cyt c via the modulation of levels of CLOOH in the mitochondria.
Kazuhiro Nomura, H Imai, T Koumura, T Kobayashi and Y Nakagawa : Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis., The Biochemical journal, Vol.351, No.Pt 1, 183-193, 2000.
(Summary)
Cytochrome c (cyt. c) is a proapoptotic factor that binds preferentially to cardiolipin (CL), a mitochondrial lipid, but not to cardiolipin hydroperoxide (CL-OOH). Cyt. c that had bound to CL liposomes was liberated on peroxidation of the liposomes by a radical. The generation of CL-OOH in mitochondria occurred before the release of cyt. c in rat basophile leukaemia (RBL)2H3 cells that had been induced to undergo apoptosis by exposure to hypoglycaemia with 2-deoxyglucose (2DG). The amount of cyt. c bound to CL prepared from the mitochondria of 2DG-treated cells was lower than that of untreated cells. The release of cyt. c was completely suppressed when the production of CL-OOH in mitochondria was inhibited by the overexpression of mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx). The fluorescence from CL-labelling dye (10-N-nonyl Acridine Orange) decreased on the induction of apoptosis by 2DG. However, no decrease in fluorescence was observed in PHGPx-overexpressing cells. Cyt. c was released from mitochondria that had been isolated from control cells on peroxidation by t-butylhydroperoxide, but no similar liberation of cyt. c from mitochondria isolated from mitochondrial PHGPx-overexpressing cells was observed. These findings suggest that the generation of CL-OOH in mitochondria might be a primary event that triggers the release of cyt. c from mitochondria in the apoptotic process in which mitochondrial PHGPx participates as an anti-apoptotic factor by preventing the formation of CL-OOH.
Kazuhiro Nomura, H Imai, T Koumura, M Arai and Y Nakagawa : Mitochondrial phospholipid hydroperoxide glutathione peroxidase suppresses apoptosis mediated by a mitochondrial death pathway., The Journal of biological chemistry, Vol.274, No.41, 29294-29302, 1999.
(Summary)
Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is a key enzyme in the protection of biomembranes exposed to oxidative stress. We investigated the role of mitochondrial PHGPx in apoptosis using RBL2H3 cells that overexpressed mitochondrial PHGPx (M15 cells), cells that overexpressed non-mitochondrial PHGPx (L9 cells), and control cells (S1 cells). The morphological changes and fragmentation of DNA associated with apoptosis occurred within 15 h in S1 and L9 cells upon exposure of cells to 2-deoxyglucose (2DG). The release of cytochrome c from mitochondria was observed in S1 cells after 4 h and was followed by the activation of caspase-3 within 6 h. Overexpression of mitochondrial PHGPx prevented the release of cytochrome c, the activation of caspase-3, and apoptosis, but non-mitochondrial PHGPx lacked the ability to prevent the induction of apoptosis by 2DG. An ability to protect cells from 2DG-induced apoptosis was abolished when the PHGPx activity of M15 cells was inhibited by diethylmalate, indicating that the resistance of M15 cells to apoptosis was indeed due to the overexpression of PHGPx in the mitochondria. The expression of members of the Bcl-2 family of proteins, such as Bcl-2, Bcl-xL, Bax, and Bad, was unchanged by the overexpression of PHGPx in cells. The levels of hydroperoxides, including hydrogen and lipid peroxide, in mitochondria isolated from S1 and L9 cells were significantly increased after the exposure to 2DG for 2 h, while the level of hydroperoxide in mitochondria isolated from M15 cells was lower than that in S1 and L9 cells. M15 cells were also resistant to apoptosis induced by etoposide, staurosporine, UV irradiation, cycloheximide, and actinomycin D, but not to apoptosis induced by Fas-specific antibodies, which induces apoptosis via a pathway distinct from the pathway initiated by 2DG. Our results suggest that hydroperoxide, produced in mitochondria, is a major factor in apoptosis and that mitochondrial PHGPx might play a critical role as an anti-apoptotic agent in mitochondrial death pathways.
M Arita, Kazuhiro Nomura, H Arai and K Inoue : alpha-tocopherol transfer protein stimulates the secretion of alpha-tocopherol from a cultured liver cell line through a brefeldin A-insensitive pathway., Proceedings of the National Academy of Sciences of the United States of America, Vol.94, No.23, 12437-12441, 1997.
(Summary)
Vitamin E (alpha-tocopherol) is a fat-soluble antioxidant that is transported by plasma lipoproteins in the body. alpha-Tocopherol taken up by the liver with lipoprotein is thought to be resecreted into the plasma in very low density lipoprotein (VLDL). alpha-Tocopherol transfer protein (alphaTTP), which was recently identified as a product of the causative gene for familial isolated vitamin E deficiency, is a cytosolic liver protein and plays an important role in the efficient recycling of plasma vitamin E. To throw light on the mechanism of alphaTTP-mediated alpha-tocopherol transfer in the liver cell, we devised an assay system using the hepatoma cell line McARH7777. Using this system, we found that the secretion of alpha-tocopherol was more efficient in cells expressing alphaTTP than in matched cells lacking alphaTTP. Brefeldin A, which effectively inhibits VLDL secretion by disrupting the Golgi apparatus, had no effect on alpha-tocopherol secretion, indicating that alphaTTP-mediated alpha-tocopherol secretion is not coupled to VLDL secretion. Among other agents tested, only 25-hydroxycholesterol, a modulator of cholesterol metabolism, inhibited alpha-tocopherol secretion. This inhibition is most likely mediated by oxysterol-binding protein. These results suggest that alphaTTP present in the liver cytosol functions to stimulate secretion of cellular alpha-tocopherol into the extracellular medium and that the reaction utilizes a novel non-Golgi-mediated pathway that may be linked to cellular cholesterol metabolism and/or transport.
(Keyword)
Animals / Brefeldin A / Carrier Proteins / Cyclopentanes / Gene Expression / Liver / Liver Neoplasms, Experimental / Rats / Signal Transduction / Tumor Cells, Cultured / Vitamin E
佐久間 洋二朗, 奈部 浩一郎, 本庶 祥子, 池田 弘毅, 青山 倫久, 木村 哲也, Kazuhiro Nomura, 浜本 芳之, 和田 良春 and 越山 裕行 : A case record of a patient with diabetes mellitus and MEN1, 糖尿病診療マスター, Vol.6, No.3, 309-313, 2008.
K Nabe, S Honjo, H Ikeda, Y Wada, Kazuhiro Nomura, Y Hamamoto, T Koh, Y Tatsuoka and H Koshiyama : Diabetes insipidus and cognitive function., Medical Hypotheses, Vol.69, No.4, 764-766, Apr. 2007.
(Summary)
It has been well known that several neuropeptides may affect human behavior, and that some endocrinopathies are associated with impaired higher function of the brain. There have been increasing evidences that vasopressin has both peripheral and central effects, the latter of which is involved in memory. In experimental animals, male mice with a null mutation in the V1a receptor (V1aR) exhibit a profound impairment in social recognition and changes in anxiety-like behavior. An AVP fragment analog has been reported to facilitate memory retention and recall in mice through protein kinase C-independent pathways. In human, a few recent reports have suggested that a familial central diabetes insipidus, caused by a heterozygous mutation in the gene for vasopressin prohormone, have minor disturbances in central nervous system. Taken together, it is hypothesized that the subject with central diabetes insipidus may frequently present with an impaired cognitive ability. It is justified to examine the cognitive function, when we make a diagnosis of central diabetes insipidus and to perform a clinical study to investigate whether central diabetes insipidus may be associated with impairment of higher brain functions.
M Noda, Kazuhiro Nomura, Y Asou, H Nemoto, M Ishijima, M Takamoto, M Usui and K Kashimada : [Bone metabolism and angiogenesis]., Clinical calcium, Vol.11, No.4, 404-410, Apr. 2001.
(Summary)
Bone metabolism is regulated not only by the nutrition supplied by vessel but also by the signals from the cells in vascular tissues. Identification of such signaling molecules has been the major issue in the field of research on the relationship between bone and vasculatures. This review touches on the recent findings on the expression and functions of such signaling molecules including VEGF, MMP and non-collagenous bone matrix proteins.
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15775533
Kazuhiro Nomura, H Imai, T Koumura and Y Nakagawa : Involvement of mitochondrial phospholipid hydroperoxide glutathione peroxidase as an antiapoptotic factor., Biological signals and receptors, Vol.10, No.1-2, 81-92, 2001.
(Summary)
Although reactive oxygen species (ROS) such as superoxide and hydroperoxide are known to induce apoptotic cell death, little is known as to the apoptotic death signaling of mitochondrial ROS. Recent evidence has suggested that antioxidant enzymes in mitochondria may be responsible for the regulation of cytochrome c release and apoptotic cell death. This paper examines the current state of knowledge regarding the role of mitochondrial antioxidant enzymes, especially phospholipid hydroperoxide glutathione peroxidase. A model for the release of cytochrome c by lipid hydroperoxide has also been proposed.
K Uchiyama, Y Hirata, Kazuhiro Nomura, H Wijaya, M Taniguchi, S Kitaoka, T Furuyashiki and W Ogawa : Mental stress induces muscle atrophy through brain inflammation and the C/EBPβδ pathway in skeletal muscle, The 50th European Muscle Conference, Sep. 2023.
2.
K Hozumi, K Sugawara, Y Hirata, Kazuhiro Nomura and W Ogawa : Effects of Imeglimin on Mitochondrial Function, AMPK Activation, and Gene Expression in Hepatocytes and Myocytes, The 50th European Muscle Conference, Sep. 2023.
3.
T Inoue, Y Hirata, Kazuhiro Nomura and W Ogawa : Role of myofiber Piezo1 in skeletal muscle hypertrophy induced by mechanical load, The 50th European Muscle Conference, Sep. 2023.
4.
Y Hirata, Kazuhiro Nomura and W Ogawa : A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy, The 50th European Muscle Conference, Sep. 2023.
Proceeding of Domestic Conference:
1.
Kazuhiro Nomura and 小川 渉 : 運動療法に抵抗性を示す痩せにくい肥満, 第67回日本糖尿病学会年次学術集会シンポジウム, May 2024.