Remodelling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
- National University of Singapore (NUS), Singapore
- Singapore Bioimaging Consortium, Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
- National University of Singapore NUS), Singapore
- Lund University, Sweden
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 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.
Data availability
Raw sequencing data is available at NCBI GEO under accession number GSE159498.
Article and author information
Author details
Funding
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.
Ethics
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.
Copyright
© 2020, Ow et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,429
- views
-
- 370
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Remodelling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
eLife 9:e63835.
https://doi.org/10.7554/eLife.63835
Further reading
-
- Cell Biology
Prostaglandin E2 (PGE2) is an endogenous inhibitor of glucose-stimulated insulin secretion (GSIS) and plays an important role in pancreatic β-cell dysfunction in type 2 diabetes mellitus (T2DM). This study aimed to explore the underlying mechanism by which PGE2 inhibits GSIS. Our results showed that PGE2 inhibited Kv2.2 channels via increasing PKA activity in HEK293T cells overexpressed with Kv2.2 channels. Point mutation analysis demonstrated that S448 residue was responsible for the PKA-dependent modulation of Kv2.2. Furthermore, the inhibitory effect of PGE2 on Kv2.2 was blocked by EP2/4 receptor antagonists, while mimicked by EP2/4 receptor agonists. The immune fluorescence results showed that EP1–4 receptors are expressed in both mouse and human β-cells. In INS-1(832/13) β-cells, PGE2 inhibited voltage-gated potassium currents and electrical activity through EP2/4 receptors and Kv2.2 channels. Knockdown of Kcnb2 reduced the action potential firing frequency and alleviated the inhibition of PGE2 on GSIS in INS-1(832/13) β-cells. PGE2 impaired glucose tolerance in wild-type mice but did not alter glucose tolerance in Kcnb2 knockout mice. Knockout of Kcnb2 reduced electrical activity, GSIS and abrogated the inhibition of PGE2 on GSIS in mouse islets. In conclusion, we have demonstrated that PGE2 inhibits GSIS in pancreatic β-cells through the EP2/4-Kv2.2 signaling pathway. The findings highlight the significant role of Kv2.2 channels in the regulation of β-cell repetitive firing and insulin secretion, and contribute to the understanding of the molecular basis of β-cell dysfunction in diabetes.
-
- Cell Biology
Existence of cilia in the last eukaryotic common ancestor raises a fundamental question in biology: how the transcriptional regulation of ciliogenesis has evolved? One conceptual answer to this question is by an ancient transcription factor regulating ciliary gene expression in both uni- and multicellular organisms, but examples of such transcription factors in eukaryotes are lacking. Previously, we showed that an ancient transcription factor X chromosome-associated protein 5 (Xap5) is required for flagellar assembly in Chlamydomonas. Here, we show that Xap5 and Xap5-like (Xap5l) are two conserved pairs of antagonistic transcription regulators that control ciliary transcriptional programs during spermatogenesis. Male mice lacking either Xap5 or Xap5l display infertility, as a result of meiotic prophase arrest and sperm flagella malformation, respectively. Mechanistically, Xap5 positively regulates the ciliary gene expression by activating the key regulators including Foxj1 and Rfx families during the early stage of spermatogenesis. In contrast, Xap5l negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage. Our results provide new insights into the mechanisms by which temporal and spatial transcription regulators are coordinated to control ciliary transcriptional programs during spermatogenesis.
