Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts

(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver its...

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Main Authors:	Sreepradha Eswaran, Anshu Babbar, Hannah K. Drescher, Thomas C. A. Hitch, Thomas Clavel, Moritz Muschaweck, Thomas Ritz, Daniela C. Kroy, Christian Trautwein, Norbert Wagner, Angela Schippers
Format:	Article
Language:	English
Published:	MDPI AG 2021-07-01
Series:	International Journal of Molecular Sciences
Subjects:	L-selectin Nrf2 Keap1 NAFLD cellular migration microbiota
Online Access:	https://www.mdpi.com/1422-0067/22/14/7314

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spelling	doaj-cd59335df98d4b71b1f6555c8048aaa52021-07-23T13:45:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-01227314731410.3390/ijms22147314Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota ShiftsSreepradha Eswaran0Anshu Babbar1Hannah K. Drescher2Thomas C. A. Hitch3Thomas Clavel4Moritz Muschaweck5Thomas Ritz6Daniela C. Kroy7Christian Trautwein8Norbert Wagner9Angela Schippers10Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, GermanyDepartment of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, GermanyDivision of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USAFunctional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, GermanyFunctional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, GermanyDepartment of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, GermanyInstitute of Pathology, Ruprecht-Karls-University Heidelberg, D-69117 Heidelberg, GermanyDepartment of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, GermanyDepartment of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, GermanyDepartment of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, GermanyDepartment of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel<sup>−/−</sup>Keap1<sup>flx/flx</sup>) and littermates with selective hepatic Keap1 deletion (Lsel<sup>−/−</sup>Keap1<sup>Δhepa</sup>) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel<sup>−/−</sup>Keap1<sup>Δhepa</sup> mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel<sup>−/−</sup>Keap1<sup>flx/flx</sup> littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.https://www.mdpi.com/1422-0067/22/14/7314L-selectinNrf2Keap1NAFLDcellular migrationmicrobiota
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Sreepradha Eswaran Anshu Babbar Hannah K. Drescher Thomas C. A. Hitch Thomas Clavel Moritz Muschaweck Thomas Ritz Daniela C. Kroy Christian Trautwein Norbert Wagner Angela Schippers
spellingShingle	Sreepradha Eswaran Anshu Babbar Hannah K. Drescher Thomas C. A. Hitch Thomas Clavel Moritz Muschaweck Thomas Ritz Daniela C. Kroy Christian Trautwein Norbert Wagner Angela Schippers Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts International Journal of Molecular Sciences L-selectin Nrf2 Keap1 NAFLD cellular migration microbiota
author_facet	Sreepradha Eswaran Anshu Babbar Hannah K. Drescher Thomas C. A. Hitch Thomas Clavel Moritz Muschaweck Thomas Ritz Daniela C. Kroy Christian Trautwein Norbert Wagner Angela Schippers
author_sort	Sreepradha Eswaran
title	Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts
title_short	Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts
title_full	Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts
title_fullStr	Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts
title_full_unstemmed	Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts
title_sort	upregulation of anti-oxidative stress response improves metabolic changes in l-selectin-deficient mice but does not prevent nafld progression or fecal microbiota shifts
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1661-6596 1422-0067
publishDate	2021-07-01
description	(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel<sup>−/−</sup>Keap1<sup>flx/flx</sup>) and littermates with selective hepatic Keap1 deletion (Lsel<sup>−/−</sup>Keap1<sup>Δhepa</sup>) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel<sup>−/−</sup>Keap1<sup>Δhepa</sup> mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel<sup>−/−</sup>Keap1<sup>flx/flx</sup> littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.
topic	L-selectin Nrf2 Keap1 NAFLD cellular migration microbiota
url	https://www.mdpi.com/1422-0067/22/14/7314
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Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts

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