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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...

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Autores principales: Oba, Daiju, Inoue, Shin-ichi, Miyagawa-Tomita, Sachiko, Nakashima, Yasumi, Niihori, Tetsuya, Yamaguchi, Seiji, Matsubara, Yoichi, Aoki, Yoko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
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.
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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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