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

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 ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning b-oxidation, reflected by increased acylcarnitines and reduced b-hydroxybutyrate. This led to elevated plasma free fatty acids, 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 possibly causative for liver pathology.

Cadez, Matias JA*Star Institute of Molecular and Cell Biology (IMCB) (author)
Zafer, GözdeA*Star Institute of Molecular and Cell Biology (IMCB) (author)
Foo, Juat ChinNational University of Singapore (author)
Li, Hong YuAgency for Science, Technology and Research (A*STAR) (author)
Ghosh, SoumitaNational University of Singapore (author)
Wollmann, HeikeA*Star Institute of Molecular and Cell Biology (IMCB) (author)
Cazenave-Gassiot, AmauryNational University of Singapore (author)
Ong, Chee BingA*Star Institute of Molecular and Cell Biology (IMCB) (author)
Wenk, Markus RNational University of Singapore (author)
Han, WeipingA*Star Institute of Molecular and Cell Biology (IMCB) (author)
Choi, HyungwonNational University of Singapore (author)
Kaldis, PhilippLund University,Lunds universitet,Metabolism och leversjukdomar,Forskargrupper vid Lunds universitet,Metabolic disorders and liver disease,Lund University Research Groups(Swepub:lu)ph6235ka (author)
A*Star Institute of Molecular and Cell Biology (IMCB)National University of Singapore (creator_code:org_t)

By the author/editor: Ow, Jin Rong; Cadez, Matias J; Zafer, Gözde; Foo, Juat Chin; Li, Hong Yu; Ghosh, Soumita; show more...; Wollmann, Heike; Cazenave-Gassiot ...; Ong, Chee Bing; Wenk, Markus R; Han, Weiping; Choi, Hyungwon; Kaldis, Philipp; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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