Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division.

Jin Rong Ow,Amaury Cazenave-Gassiot,Hong Yu Li,Matias J Caldez,Gözde Zafer,Heike Wollmann,Chee Bing Ong,Weiping Han,Soumita Ghosh,Hyungwon Choi,Juat Chin Foo,Markus R Wenk,Philipp Kaldis

doi:10.7554/elife.63835

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 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.

Highlights

Lipid metabolism is closely linked to cell proliferation, especially since cell division requires the synthesis of phospholipids (PLs) that make up the plasma membrane
This was despite both control and Cdk1 cKO mice eating the same amount of food (Figure 1C; p=0.6825), implying that this change was not due to a difference in food intake
When we probed Cdk1 cKO white adipose tissue (WAT) for the expression of genes involved with fatty acid synthesis, we found that Acaca, Fasn, and Scd1 were decreased (Figure 3I–J), implying that the increase in TGs was not due to increases in WAT fatty acid synthesis

Summary

Introduction

Lipid metabolism is closely linked to cell proliferation, especially since cell division requires the synthesis of phospholipids (PLs) that make up the plasma membrane. It was discovered that de novo fatty acid synthesis was essential to provide the fatty acids needed for PL synthesis because inhibition of fatty acid synthesis led to cell cycle arrest at the G2/M transition and prevented the exit from mitosis (Scaglia et al, 2014). This was supported by the finding that enzymes involved in fatty acid synthesis were more thermally stable in mitosis and early G1 phase (Becher et al, 2018).

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Results

Conclusion