Document Detail


Lack of mutations in LMNA, its promoter region, and the cellular retinoic acid binding protein II (CRABP II) in HIV associated lipodystrophy.
MedLine Citation:
PMID:  12844477     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Familial partial lipodystrophy (FPL) and lipodystrophy observed in HIV-1 infected patients receiving highly active antiretroviral therapy (HAART) share multiple clinical and metabolic features. Recently, missense mutations of LMNA encoding lamin A/C have been described in FPL providing evidence for a pivotal role of lamin A/C in the regulation of adipocytes. Moreover, the cellular retinoic acid binding protein (CRABP) has been suggested to be involved in HAART associated lipodystrophy. In this study, we excluded mutations within the complete coding region and the promoter of LMNA and the CRABP II gene in HIV-1 infected patients with lipodystrophy and also any correlation of the nucleotide polymorphism at codon 566 in exon 10 of LMNA with metabolic abnormalities. Protease inhibitors including indinavir have been shown to reduce adipocyte cell differentiation and increase apoptosis of adipocytes in vitro. Indinavir leads to altered retinoic acid signaling most likely by an activation of the RAR/RXR heterodimer, perhaps by displacing all-trans-retinoic acid from CRABP. Since LMNA is regulated by a retinoic acid responsive element (L-RARE) in the promoter region, we propose that indinavir impairs retinoic acid homeostasis and/or interact via the L-RARE within the LMNA promoter. This results in altered LMNA expression and subsequent impaired adipocyte differentiation, lipodystrophic body habitus, and metabolic disturbances in HIV infected patients receiving HAART.
Authors:
G M N Behrens; J Genschel; R E Schmidt; H H-J Schmidt
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of medical research     Volume:  8     ISSN:  0949-2321     ISO Abbreviation:  Eur. J. Med. Res.     Publication Date:  2003 May 
Date Detail:
Created Date:  2003-07-07     Completed Date:  2004-02-03     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9517857     Medline TA:  Eur J Med Res     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  221-5     Citation Subset:  IM    
Affiliation:
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, IG Royal Parade, Parkville 3050, Victoria, Australia. behrens@wehi.edu.au
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Antiretroviral Therapy, Highly Active / adverse effects
HIV Infections / complications*,  drug therapy
HIV Protease / genetics
Humans
Laminin / genetics*
Lipodystrophy / complications,  genetics*,  pathology
Models, Biological
Mutation
Polymorphism, Single Nucleotide
Promoter Regions, Genetic*
Receptors, Retinoic Acid / chemistry,  genetics*,  metabolism
Sequence Homology, Amino Acid
Chemical
Reg. No./Substance:
0/Laminin; 0/Receptors, Retinoic Acid; 0/retinoic acid binding protein II, cellular; 151186-83-3/laminin A; EC 3.4.23.-/HIV Protease

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