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However, the role of LAL in diet-induced adaptations is largely unexplored. In this study, we demonstrate that feeding a Western-type diet to Lal-deficient (LAL-KO) mice triggers metabolic reprogramming that modulates gut-liver cholesterol homeostasis. Induction of ileal fibroblast growth factor 15 (three-fold), absence of hepatic cholesterol 7\u03b1-hydroxylase expression, and activation of the ERK phosphorylation cascade results in altered bile acid composition, substantial changes in the gut microbiome, reduced nutrient absorption by 40%, and two-fold increased fecal lipid excretion in LAL-KO mice. These metabolic adaptations lead to impaired bile acid synthesis, lipoprotein uptake, and cholesterol absorption and ultimately to the resistance of LAL-KO mice to diet-induced obesity. Our results indicate that LAL-derived lipolytic products might be important metabolic effectors in the maintenance of whole-body lipid homeostasis.<\/jats:p>","DOI":"10.3390\/cells10102619","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T10:55:40Z","timestamp":1633085740000},"page":"2619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase"],"prefix":"10.3390","volume":"10","author":[{"given":"Vinay","family":"Sachdev","sequence":"first","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina","family":"Duta-Mare","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7609-9436","authenticated-orcid":false,"given":"Melanie","family":"Korbelius","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-7799","authenticated-orcid":false,"given":"Nemanja","family":"Vuji\u0107","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Leopold","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6759-3291","authenticated-orcid":false,"given":"Jan","family":"Freark de Boer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Medical Center Groningen, 9713 Groningen, The Netherlands"},{"name":"Department of Laboratory Medicine, University Medical Center Groningen, 9713 Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Rainer","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Fickert","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Kolb","sequence":"additional","affiliation":[{"name":"Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, 8010 Graz, Austria"},{"name":"Center for Medical Research Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2518-737X","authenticated-orcid":false,"given":"Folkert","family":"Kuipers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Medical Center Groningen, 9713 Groningen, The Netherlands"},{"name":"Department of Laboratory Medicine, University Medical Center Groningen, 9713 Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6196-4255","authenticated-orcid":false,"given":"Branislav","family":"Radovic","sequence":"additional","affiliation":[{"name":"Gottfried Schatz 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Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1146\/annurev.cellbio.24.110707.175344","article-title":"Coordination of Lipid Metabolism in Membrane Biogenesis","volume":"25","author":"Nohturfft","year":"2009","journal-title":"Annu. 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