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.
Raw sequencing data is available at NCBI GEO under accession number GSE159498.
Remodelling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of hepatic CDK1 and hepatocyte divisionNCBI Gene Expression Omnibus, GSE159498.
The work was supported in part by the Faculty of Medicine, Lund University to PK, the Biomedical Research Council, Agency for Science, Technology and Research (A*STAR) to PK and to AC-G and MRW (IAF-ICP I1901E0040); by SINGA (Singapore International Graduate Award) to GZ; by the National Medical Research Council Singapore, NMRC (NMRC/CBRG/0091/2015) to PK; by National Research Foundation Singapore grant (NRF2016-CRP001-103) to PK; by the National Medical Research Council of Singapore (NMRC-CG-M009 to H.C.); by grants from the National University of Singapore via the Life Sciences Institute to JCF; the Swedish Foundation for Strategic Research Dnr IRC15-0067; and Swedish Research Council, Strategic Research Area EXODIAB, Dnr 2009-1039. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were performed in accordance to protocols (#171268) approved by the A*STAR Institutional Animal Care and Use Committee (IACUC) based on the National Advisory Committee for Laboratory Animal Research (NACLAR) Guidelines.
- David E James, The University of Sydney, Australia
© 2020, Ow et al.
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