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

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

研究成果: Article査読

16 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)138-150
ページ数13
ジャーナルEBioMedicine
27
DOI
出版ステータスPublished - 2018 1

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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