MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice.

Scientific Reports
Pierre S LeclèreMichèle Teboul

Abstract

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor.

References

Jan 16, 1999·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·J CórdobaA T Blei
Nov 26, 1999·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·A RibeiroG J Gores
Jun 5, 2003·Journal of the National Cancer Institute·Eva S SchernhammerGraham A Colditz
Apr 23, 2005·Science·Fred W TurekJoseph Bass
Nov 1, 2006·Laboratory Investigation; a Journal of Technical Methods and Pathology·Isabelle A LeclercqYves J Horsmans
Apr 9, 2008·Cell Metabolism·Kimihiko MatsusueFrank J Gonzalez
Jan 21, 2010·BioFactors·Malayannan SubramaniamThomas C Spelsberg
Apr 14, 2010·Molecular and Cellular Biology·Fabienne GuillaumondMichèle Teboul
Aug 23, 2011·Biochemical and Biophysical Research Communications·Katsumi IizukaYukio Horikawa
Sep 8, 2011·The EMBO Journal·Di MaJiandie D Lin
Mar 13, 2012·Cell Metabolism·Darwin JeyarajMukesh K Jain
May 9, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Julien DelezieEtienne Challet
May 25, 2012·Chronobiology International·Philip TuckerYolande Esquirol
Aug 17, 2012·Proceedings of the National Academy of Sciences of the United States of America·Mary L SpenglerMarina P Antoch
Nov 28, 2012·Journal of Hepatology·Huabing ZhangYongsheng Chang
Jan 29, 2013·Journal of Hepatology·Lars P BechmannScott L Friedman
Mar 28, 2013·American Journal of Physiology. Endocrinology and Metabolism·Johanna L BarclayHenrik Oster
Dec 24, 2013·Cell·Kristin L Eckel-MahanPaolo Sassone-Corsi
Jan 8, 2014·Genes & Development·Jerome S MenetMichael Rosbash
Jun 26, 2014·EMBO Molecular Medicine·Jérémie GautheronTom Luedde
Aug 16, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Xu XuAnn-Hwee Lee
Oct 29, 2014·Proceedings of the National Academy of Sciences of the United States of America·Ray ZhangJohn B Hogenesch
Jun 5, 2015·Nature Communications·Sean Shuxin HanMukesh K Jain
Oct 17, 2015·American Journal of Physiology. Gastrointestinal and Liver Physiology·Konstantinos A PapadakisWilliam A Faubion
Dec 29, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Zobair M YounossiMark Wymer
Mar 5, 2016·PloS One·Céline FeilletMichèle Teboul
May 8, 2016·Cell·Selma MasriPaolo Sassone-Corsi
May 25, 2016·Current Biology : CB·Till Roenneberg, Martha Merrow
Aug 11, 2016·Diabetes·Ze ZhengKezhong Zhang
Oct 16, 2016·The Journal of Cell Biology·Amandine ChaixSatchidananda Panda
Nov 26, 2016·Science·Satchidananda Panda
Nov 28, 2016·Cancer Cell·Nicole M KettnerLoning Fu
Feb 22, 2017·Nature Reviews. Nephrology·Giovanni Targher, Christopher D Byrne
Mar 23, 2017·Journal of Hepatology·Stéphanie PatourauxPhilippe Gual
Apr 22, 2017·Nature Reviews. Gastroenterology & Hepatology·Nina L GluchowskiRobert V Farese

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Citations

Jan 6, 2021·International Journal of Molecular Sciences·Junghoon LeeJi-Young Cha

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Methods Mentioned

BETA
flow cytometry
transfection
PCR
fluorescence activated cell sorting
Protein assay

Software Mentioned

FlowJo
HALO
R

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