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

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)138-150
Number of pages13
JournalEBioMedicine
Volume27
DOIs
Publication statusPublished - 2018 Jan

Keywords

  • Cancer metabolism
  • Costello syndrome
  • Diet-induced obesity
  • ERK
  • Hras G12S
  • Mitochondrial fatty acid oxidation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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