RRC ID 49646
Author Oba D, Inoue SI, Miyagawa-Tomita S, Nakashima Y, Niihori T, Yamaguchi S, Matsubara Y, Aoki Y.
Title Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis.
Journal EBioMedicine
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.
Volume 27
Pages 138-150
Published 2018-1-1
DOI 10.1016/j.ebiom.2017.11.029
PII S2352-3964(17)30445-0
PMID 29254681
PMC PMC5828294
MeSH Animals Carnitine / analogs & derivatives Carnitine / metabolism Diet, High-Fat Energy Metabolism* / genetics Face / abnormalities Fatty Acids / metabolism Female Gene Expression Regulation Gene Knock-In Techniques Glucose / metabolism Glutamine / metabolism Homeostasis* Hypertrophy Kidney / abnormalities Kidney / pathology Liver / blood supply Liver / metabolism* Mice Mitochondria / metabolism Mutation / genetics* Myocytes, Cardiac / pathology Obesity / genetics* Obesity / metabolism Oncogenes* Oxidation-Reduction Phenotype Proto-Oncogene Proteins p21(ras) / genetics* Proto-Oncogene Proteins p21(ras) / metabolism Weight Gain ras Proteins / genetics* ras Proteins / metabolism
IF 5.736
Times Cited 9
Mice RBRC01828