Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division.
Elife
; 92020 12 21.
Article
em En
| MEDLINE
| ID: mdl-33345777
ABSTRACT
Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning ß-oxidation, reflected by increased acylcarnitines (ACs) and reduced ß-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Divisão Celular
/
Proteína Quinase CDC2
/
Hepatócitos
/
Metabolismo dos Lipídeos
/
Hiperinsulinismo
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Elife
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Singapura