{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T06:15:48Z","timestamp":1775888148035,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK085176; R01DK111052; R01DK116496"],"award-info":[{"award-number":["R01DK085176; R01DK111052; R01DK116496"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR002378"],"award-info":[{"award-number":["UL1TR002378"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["1-18-IBS-346"],"award-info":[{"award-number":["1-18-IBS-346"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Niemann\u2013Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-\u03b2-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7\u03b1-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.<\/jats:p>","DOI":"10.3390\/cells10123468","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T21:52:32Z","timestamp":1639086752000},"page":"3468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-7395","authenticated-orcid":false,"given":"Lin","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Biological Sciences, The University of Texas at Dallas, 800 W, Campbell Road, Richardson, TX 75080, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinyan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie","family":"Haywood","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingzhong","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Biology, Georgia State University, Atlanta, GA 30303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biology, Georgia State University, Atlanta, GA 30303, USA"},{"name":"Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9760-4422","authenticated-orcid":false,"given":"Paul A.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5186-9182","authenticated-orcid":false,"given":"Liqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1006\/geno.2000.6151","article-title":"Evidence for a Niemann-pick C (NPC) gene family: Identification and characterization of NPC1L1","volume":"65","author":"Davies","year":"2000","journal-title":"Genomics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1126\/science.1093131","article-title":"Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption","volume":"303","author":"Altmann","year":"2004","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33586","DOI":"10.1074\/jbc.M405817200","article-title":"Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis","volume":"279","author":"Davis","year":"2004","journal-title":"J. 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