Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division.
Jin Rong OwMatias J CaldezGözde ZaferJuat Chin FooHong Yu LiSoumita GhoshHeike WollmannAmaury Cazenave-GassiotChee Bing OngMarkus R WenkWeiping HanHyung Won ChoiPhilipp KaldisPublished in: eLife (2020)
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 β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-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.
Keyphrases
- cell cycle
- cell proliferation
- fatty acid
- rna seq
- signaling pathway
- adipose tissue
- insulin resistance
- liver injury
- oxidative stress
- mouse model
- single cell
- pi k akt
- type diabetes
- high fat diet
- poor prognosis
- acute coronary syndrome
- mass spectrometry
- dna damage
- ischemia reperfusion injury
- induced apoptosis
- polycystic ovary syndrome
- binding protein