{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:31:16Z","timestamp":1777555876117,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,3,24]],"date-time":"2018-03-24T00:00:00Z","timestamp":1521849600000},"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":["INST264-95-1"],"award-info":[{"award-number":["INST264-95-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KU3280\/1-1"],"award-info":[{"award-number":["KU3280\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niemann\u2013Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-\u03b2-cyclodextrin (HP\u03b2CD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HP\u03b2CD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1\u2212\/\u2212 mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., ppar\u03b1 and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to ppar\u03b1- and acox1-associated lipolysis\/\u03b2-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HP\u03b2CD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.<\/jats:p>","DOI":"10.3390\/ijms19040972","type":"journal-article","created":{"date-parts":[[2018,3,26]],"date-time":"2018-03-26T03:43:29Z","timestamp":1522035809000},"page":"972","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann\u2013Pick-Disease Type C1"],"prefix":"10.3390","volume":"19","author":[{"given":"Lynn","family":"Ebner","sequence":"first","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Gl\u00e4ser","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, Gertrudenstra\u00dfe 9, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Br\u00e4uer","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, Gertrudenstra\u00dfe 9, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4538-877X","authenticated-orcid":false,"given":"Martin","family":"Witt","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, Gertrudenstra\u00dfe 9, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Wree","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, Gertrudenstra\u00dfe 9, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arndt","family":"Rolfs","sequence":"additional","affiliation":[{"name":"Albrecht Kossel Institute for Neuroregeneration, Rostock University Medical Center, Gehlsheimer Stra\u00dfe 20, 18147 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2517-4440","authenticated-orcid":false,"given":"Marcus","family":"Frank","sequence":"additional","affiliation":[{"name":"Medical Biology and Electron Microscopy Center, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte","family":"Vollmar","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Kuhla","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1002\/jcb.21200","article-title":"Characterization of liver disease and lipid metabolism in the Niemann-Pick C1 mouse","volume":"101","author":"Garver","year":"2007","journal-title":"J. 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