| Hypercholesterolemia in rats with hepatomas: increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol. | |
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MedLine Citation:
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PMID: 16941710 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypercholesterolemia is an important paraneoplastic syndrome in patients with hepatoma, but the nature of this defect has not yet been identified. We investigated the molecular mechanisms of hypercholesterolemia in a hepatoma-bearing rat model. Buffalo rats were implanted in both flanks with Morris hepatoma 7777 (McA-RH7777) cells. After 4 weeks, tumor weight was 5.5+/-1.7 g, and serum cholesterol level increased from 60+/-2 to 90+/-2 mg/dL. Protein and mRNA expression of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) was markedly higher in tumors than in livers. These increases were associated with activation of liver X receptor alpha (LXRalpha) as a result of the increased tissue oxysterol concentrations. The accumulation of oxysterols in the hepatomas appeared to be caused mainly by the upregulation of cholesterol biosynthesis, despite the increased tissue sterol concentrations. Overexpression of the sterol regulatory element-binding protein (SREBP) processing system relative to sterol concentration contributed to the resistance to sterols in this tumor. In addition, bile acid biosynthesis was inhibited despite the reduced expression of the small heterodimer partner (SHP) and activated LXRalpha, which also appeared to contribute to the accumulation of oxysterols followed by the acceleration of cholesterol efflux. In conclusion, hypercholesterolemia in McA-RH7777 hepatoma-bearing rats was caused by increased cholesterol efflux from tumors as a result of activation of LXRalpha. Overexpression of the SREBP processing system contributed to the activation of LXRalpha by maintaining high oxysterol levels in tissue. |
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Authors:
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Takeshi Hirayama; Akira Honda; Yasushi Matsuzaki; Teruo Miyazaki; Tadashi Ikegami; Mikio Doy; Guorong Xu; Michael Lea; Gerald Salen |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 44 ISSN: 0270-9139 ISO Abbreviation: Hepatology Publication Date: 2006 Sep |
Date Detail:
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Created Date: 2006-09-04 Completed Date: 2006-09-28 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 602-11 Citation Subset: IM |
Affiliation:
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Division of Gastroenterology and Hepatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, and Kasumigaura Hospital, Ibaraki, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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genetics Animals Carcinoma, Hepatocellular / complications*, metabolism, pathology Cell Line, Tumor Cholesterol / biosynthesis* DNA-Binding Proteins / genetics*, metabolism Electrophoresis, Polyacrylamide Gel Gene Expression Regulation, Neoplastic* Hypercholesterolemia / complications, metabolism* Immunoblotting Liver Neoplasms, Experimental / complications*, metabolism, pathology Male Orphan Nuclear Receptors RNA, Neoplasm / genetics Rats Rats, Sprague-Dawley Receptors, Cytoplasmic and Nuclear / genetics*, metabolism Reverse Transcriptase Polymerase Chain Reaction Sterol Regulatory Element Binding Proteins / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DK-26756/DK/NIDDK NIH HHS; DK-56830/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABCG1 protein, human; 0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/DNA-Binding Proteins; 0/Orphan Nuclear Receptors; 0/RNA, Neoplasm; 0/Receptors, Cytoplasmic and Nuclear; 0/Sterol Regulatory Element Binding Proteins; 0/liver X receptor; 57-88-5/Cholesterol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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