Remodelling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
(2020) In eLife 9.- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2020-12-21
- type
- Contribution to journal
- publication status
- published
- subject
- in
- eLife
- volume
- 9
- article number
- e63835
- publisher
- eLife Sciences Publications
- external identifiers
-
- pmid:33345777
- scopus:85099171720
- ISSN
- 2050-084X
- DOI
- 10.7554/eLife.63835
- language
- English
- LU publication?
- yes
- additional info
- © 2020, Ow et al.
- id
- 023a7d33-db5c-4d03-98a9-41c34058e722
- date added to LUP
- 2020-12-28 10:41:12
- date last changed
- 2024-09-19 12:09:41
@article{023a7d33-db5c-4d03-98a9-41c34058e722, abstract = {{<p>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.</p>}}, author = {{Ow, Jin Rong and Cadez, Matias J and Zafer, Gözde and Foo, Juat Chin and Li, Hong Yu and Ghosh, Soumita and Wollmann, Heike and Cazenave-Gassiot, Amaury and Ong, Chee Bing and Wenk, Markus R and Han, Weiping and Choi, Hyungwon and Kaldis, Philipp}}, issn = {{2050-084X}}, language = {{eng}}, month = {{12}}, publisher = {{eLife Sciences Publications}}, series = {{eLife}}, title = {{Remodelling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division}}, url = {{http://dx.doi.org/10.7554/eLife.63835}}, doi = {{10.7554/eLife.63835}}, volume = {{9}}, year = {{2020}}, }