Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis
| Autor: | Seiji Yamaguchi, Daiju Oba, Yoko Aoki, Shin Ichi Inoue, Tetsuya Niihori, Yoichi Matsubara, Sachiko Miyagawa-Tomita, Yasumi Nakashima |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | EBioMedicine, Vol 27, Iss C, Pp 138-150 (2018) EBioMedicine |
| ISSN: | 2352-3964 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|