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

EBioMedicine

Shin-ichi Inoue¹  Yoko Aoki¹  Yoichi Matsubara¹  Daiju Oba¹  Tetsuya Niihori¹  Sachiko Miyagawa-Tomita²  Yasumi Nakashima³  Seiji Yamaguchi⁴ 

[1] Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan;Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan;Department of Pediatrics, Seirei Hamamatsu General Hospital, Shizuoka, Japan;Department of Pediatrics, Shimane University, Faculty of Medicine, Shimane, Japan;

关键词: Costello syndrome;    Hras G12S;    Mitochondrial fatty acid oxidation;    Diet-induced obesity;    Cancer metabolism;    ERK;   

DOI  :  10.1016/j.ebiom.2017.11.029

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown