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2 results on '"Daiju Oba"'

1. Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis

Author

Daiju Oba, Shin-ichi Inoue, Sachiko Miyagawa-Tomita, Yasumi Nakashima, Tetsuya Niihori, Seiji Yamaguchi, Yoichi Matsubara, and Yoko Aoki

Subjects
Costello syndrome, Hras G12S, Mitochondrial fatty acid oxidation, Diet-induced obesity, Cancer metabolism, ERK, Medicine, Medicine (General), R5-920
Abstract

Costello syndrome is a “RASopathy” that is characterized by growth retardation, dysmorphic facial appearance, hypertrophic cardiomyopathy and tumor predisposition. >80% of patients with Costello syndrome harbor a heterozygous germline G12S mutation in HRAS. Altered metabolic regulation has been suspected because patients with Costello syndrome exhibit hypoketotic hypoglycemia and increased resting energy expenditure, and their growth is severely retarded. To examine the mechanisms of energy reprogramming by HRAS activation in vivo, we generated knock-in mice expressing a heterozygous Hras G12S mutation (HrasG12S/+ mice) as a mouse model of Costello syndrome. On a high-fat diet, HrasG12S/+ mice developed a lean phenotype with microvesicular hepatic steatosis, resulting in early death compared with wild-type mice. Under starvation conditions, hypoketosis and elevated blood levels of long-chain fatty acylcarnitines were observed, suggesting impaired mitochondrial fatty acid oxidation. Our findings suggest that the oncogenic Hras mutation modulates energy homeostasis in vivo.

Published
2018
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2. Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis

Author

Seiji Yamaguchi, Daiju Oba, Yoko Aoki, Shin Ichi Inoue, Tetsuya Niihori, Yoichi Matsubara, Sachiko Miyagawa-Tomita, and Yasumi Nakashima

Subjects
0301 basic medicine, Glutamine, lcsh:Medicine, Mitochondrial fatty acid oxidation, Mitochondrion, Kidney, Weight Gain, medicine.disease_cause, Energy homeostasis, Hras G12S, Mice, 0302 clinical medicine, Costello syndrome, Homeostasis, Myocytes, Cardiac, Gene Knock-In Techniques, Mutation, lcsh:R5-920, Fatty Acids, Diet-induced obesity, General Medicine, Cancer metabolism, Mitochondria, ERK, Phenotype, Liver, 030220 oncology & carcinogenesis, Female, lcsh:Medicine (General), Oxidation-Reduction, medicine.medical_specialty, RASopathy, Diet, High-Fat, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Carnitine, Internal medicine, medicine, Animals, Obesity, HRAS, business.industry, Hypoketotic hypoglycemia, lcsh:R, Hypertrophy, Oncogenes, Failure to thrive, medicine.disease, Hypoglycemia, Glucose, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Face, ras Proteins, Commentary, Energy Metabolism, business
Abstract

Costello syndrome is a "RASopathy" that is characterized by growth retardation, dysmorphic facial appearance, hypertrophic cardiomyopathy and tumor predisposition. >80% of patients with Costello syndrome harbor a heterozygous germline G12S mutation in HRAS. Altered metabolic regulation has been suspected because patients with Costello syndrome exhibit hypoketotic hypoglycemia and increased resting energy expenditure, and their growth is severely retarded. To examine the mechanisms of energy reprogramming by HRAS activation in vivo, we generated knock-in mice expressing a heterozygous Hras G12S mutation (HrasG12S/+ mice) as a mouse model of Costello syndrome. On a high-fat diet, HrasG12S/+ mice developed a lean phenotype with microvesicular hepatic steatosis, resulting in early death compared with wild-type mice. Under starvation conditions, hypoketosis and elevated blood levels of long-chain fatty acylcarnitines were observed, suggesting impaired mitochondrial fatty acid oxidation. Our findings suggest that the oncogenic Hras mutation modulates energy homeostasis in vivo.

Published
2018

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