| Effects of fibrillar C-terminal fragment of cleaved alpha1-antitrypsin on cholesterol homeostasis in HepG2 cells. | |
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MedLine Citation:
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PMID: 9918920 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Amyloid fibrils of diverse origin are known to disturb vital cellular functions and induce cell death. In this study, the effects of amyloid fibrils from the C-terminal fragment (C-36) of cleaved alpha1-antitrypsin (AAT) on low-density lipoprotein (LDL) metabolism were investigated in HepG2 cells. Treatment of the cells with C-36 fibrils (10 micromol/L) enhanced 125I-LDL binding and uptake 10 to 15 times, and highly up-regulated levels of LDL receptor mRNA, as compared with control cells. Competition experiments using excess of unlabeled LDL and blockage experiments with a monoclonal LDL receptor antibody diminished or completely abolished the stimulatory effects of fibrils on LDL binding and LDL receptor mRNA levels, suggesting that fibrils act via the LDL receptor pathway. However, C-36 fibrils had no significant effect on [2-14C]acetate incorporation into cholesterol biosynthesis and cholesterol ester formation, but inhibited 125I-LDL degradation by 20% and reduced bile acid biosynthesis up to 48% in a dose-dependent manner. Preincubation of the cells with fibrils before the addition of LDL totally abolished the LDL inhibitory effect on unesterified cholesterol synthesis, further confirming the LDL receptors to be the target for C-36 fibrils. Moreover, the expression of sterol regulatory element binding protein-1 (SREBP-1) was found to increase twofold and more after 24 hours of incubation of the cells with several concentrations of C-36 fibrils. Our study suggests that the cytotoxicity of C-36 fibrils on HepG2 cells is associated with perturbed intracellular cholesterol homeostasis, induced through fibril-stimulated expression of the LDL receptors via the sterol-responsive element. |
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Authors:
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S Janciauskiene; S Lindgren |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 29 ISSN: 0270-9139 ISO Abbreviation: Hepatology Publication Date: 1999 Feb |
Date Detail:
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Created Date: 1999-02-16 Completed Date: 1999-02-16 Revised Date: 2006-11-15 |
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: 434-42 Citation Subset: IM |
Affiliation:
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Gastroenterology-Hepatology Division, Department of Medicine, University Hospital, Malmö, Sweden. Sabina.Janciauskiene@medforsk.mas.lu.se |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetates
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metabolism Bile Acids and Salts / biosynthesis CCAAT-Enhancer-Binding Proteins* Cholesterol / metabolism* Cholesterol Esters / metabolism DNA-Binding Proteins / metabolism Gene Expression / drug effects Hepatoblastoma / metabolism* Homeostasis* Humans Lipoproteins, LDL / metabolism Liver Neoplasms / metabolism* Nuclear Proteins / metabolism Peptide Fragments / pharmacology* RNA, Messenger / metabolism Receptors, LDL / genetics, metabolism Sterol Regulatory Element Binding Protein 1 Transcription Factors* Tumor Cells, Cultured alpha 1-Antitrypsin / chemistry, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Acetates; 0/Bile Acids and Salts; 0/CCAAT-Enhancer-Binding Proteins; 0/Cholesterol Esters; 0/DNA-Binding Proteins; 0/Lipoproteins, LDL; 0/Nuclear Proteins; 0/Peptide Fragments; 0/RNA, Messenger; 0/Receptors, LDL; 0/SREBF1 protein, human; 0/Sterol Regulatory Element Binding Protein 1; 0/Transcription Factors; 0/alpha 1-Antitrypsin; 57-88-5/Cholesterol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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