{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:10:47Z","timestamp":1760235047234,"version":"build-2065373602"},"reference-count":92,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["403224013 - SFB 1382"],"award-info":[{"award-number":["403224013 - SFB 1382"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>(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\u2212\/\u2212Keap1flx\/flx) and littermates with selective hepatic Keap1 deletion (Lsel\u2212\/\u2212Keap1\u0394hepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel\u2212\/\u2212Keap1\u0394hepa 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\u2212\/\u2212Keap1flx\/flx 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.<\/jats:p>","DOI":"10.3390\/ijms22147314","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T12:31:25Z","timestamp":1625661085000},"page":"7314","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"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"],"prefix":"10.3390","volume":"22","author":[{"given":"Sreepradha","family":"Eswaran","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anshu","family":"Babbar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany"},{"name":"Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9945-1239","authenticated-orcid":false,"given":"Hannah K.","family":"Drescher","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas C. A.","family":"Hitch","sequence":"additional","affiliation":[{"name":"Functional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Clavel","sequence":"additional","affiliation":[{"name":"Functional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moritz","family":"Muschaweck","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Ritz","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ruprecht-Karls-University Heidelberg, D-69117 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela C.","family":"Kroy","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Schippers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1002\/hep.30251","article-title":"Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis","volume":"69","author":"Younossi","year":"2019","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/hep.29085","article-title":"Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis","volume":"65","author":"Dulai","year":"2017","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.2337\/diabetes.50.8.1844","article-title":"Nonalcoholic fatty liver disease: A feature of the metabolic syndrome","volume":"50","author":"Marchesini","year":"2001","journal-title":"Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.cld.2013.09.009","article-title":"The role of diet and nutritional intervention for the management of patients with NAFLD","volume":"18","author":"Barrera","year":"2014","journal-title":"Clin. 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