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Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828294/ https://www.ncbi.nlm.nih.gov/pubmed/29254681 http://dx.doi.org/10.1016/j.ebiom.2017.11.029 |
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author | Oba, Daiju Inoue, Shin-ichi Miyagawa-Tomita, Sachiko Nakashima, Yasumi Niihori, Tetsuya Yamaguchi, Seiji Matsubara, Yoichi Aoki, Yoko |
author_facet | Oba, Daiju Inoue, Shin-ichi Miyagawa-Tomita, Sachiko Nakashima, Yasumi Niihori, Tetsuya Yamaguchi, Seiji Matsubara, Yoichi Aoki, Yoko |
author_sort | Oba, Daiju |
collection | PubMed |
description | 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 (Hras(G12S/+) mice) as a mouse model of Costello syndrome. On a high-fat diet, Hras(G12S/+) 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. |
format | Online Article Text |
id | pubmed-5828294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-58282942018-02-28 Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis Oba, Daiju Inoue, Shin-ichi Miyagawa-Tomita, Sachiko Nakashima, Yasumi Niihori, Tetsuya Yamaguchi, Seiji Matsubara, Yoichi Aoki, Yoko EBioMedicine Research Paper 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 (Hras(G12S/+) mice) as a mouse model of Costello syndrome. On a high-fat diet, Hras(G12S/+) 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. Elsevier 2017-12-06 /pmc/articles/PMC5828294/ /pubmed/29254681 http://dx.doi.org/10.1016/j.ebiom.2017.11.029 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Oba, Daiju Inoue, Shin-ichi Miyagawa-Tomita, Sachiko Nakashima, Yasumi Niihori, Tetsuya Yamaguchi, Seiji Matsubara, Yoichi Aoki, Yoko Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis |
title | Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis |
title_full | Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis |
title_fullStr | Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis |
title_full_unstemmed | Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis |
title_short | Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis |
title_sort | mice with an oncogenic hras mutation are resistant to high-fat diet-induced obesity and exhibit impaired hepatic energy homeostasis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828294/ https://www.ncbi.nlm.nih.gov/pubmed/29254681 http://dx.doi.org/10.1016/j.ebiom.2017.11.029 |
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