Remodeling 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, hepatocyte proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid...

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Autores principales:	Jin Rong Ow, Matias J Caldez, Gözde Zafer, Juat Chin Foo, Hong Yu Li, Soumita Ghosh, Heike Wollmann, Amaury Cazenave-Gassiot, Chee Bing Ong, Markus R Wenk, Weiping Han, Hyungwon Choi, Philipp Kaldis
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2020
Materias:	liver lipid metabolism insulin resistance hepatic steatosis cell cycle CDK1 Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/800dcd51bf63414c82eae688da8bc038
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spelling	oai:doaj.org-article:800dcd51bf63414c82eae688da8bc0382021-11-19T12:15:20ZRemodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division10.7554/eLife.638352050-084Xe63835https://doaj.org/article/800dcd51bf63414c82eae688da8bc0382020-12-01T00:00:00Zhttps://elifesciences.org/articles/63835https://doaj.org/toc/2050-084XCell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, hepatocyte 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 the 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.Jin Rong OwMatias J CaldezGözde ZaferJuat Chin FooHong Yu LiSoumita GhoshHeike WollmannAmaury Cazenave-GassiotChee Bing OngMarkus R WenkWeiping HanHyungwon ChoiPhilipp KaldiseLife Sciences Publications Ltdarticleliverlipid metabolisminsulin resistancehepatic steatosiscell cycleCDK1MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 9 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	liver lipid metabolism insulin resistance hepatic steatosis cell cycle CDK1 Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	liver lipid metabolism insulin resistance hepatic steatosis cell cycle CDK1 Medicine R Science Q Biology (General) QH301-705.5 Jin Rong Ow Matias J Caldez Gözde Zafer Juat Chin Foo Hong Yu Li Soumita Ghosh Heike Wollmann Amaury Cazenave-Gassiot Chee Bing Ong Markus R Wenk Weiping Han Hyungwon Choi Philipp Kaldis Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
description	Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, hepatocyte 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 the 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.
format	article
author	Jin Rong Ow Matias J Caldez Gözde Zafer Juat Chin Foo Hong Yu Li Soumita Ghosh Heike Wollmann Amaury Cazenave-Gassiot Chee Bing Ong Markus R Wenk Weiping Han Hyungwon Choi Philipp Kaldis
author_facet	Jin Rong Ow Matias J Caldez Gözde Zafer Juat Chin Foo Hong Yu Li Soumita Ghosh Heike Wollmann Amaury Cazenave-Gassiot Chee Bing Ong Markus R Wenk Weiping Han Hyungwon Choi Philipp Kaldis
author_sort	Jin Rong Ow
title	Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
title_short	Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
title_full	Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
title_fullStr	Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
title_full_unstemmed	Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
title_sort	remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of cdk1 and hepatocyte division
publisher	eLife Sciences Publications Ltd
publishDate	2020
url	https://doaj.org/article/800dcd51bf63414c82eae688da8bc038
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Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

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