Lack of mutations in LMNA, its promoter region, and the cellular retinoic acid binding protein II (CRABP II) in HIV associated lipodystrophy.
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.
Behrens
G M N
GM
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, IG Royal Parade, Parkville 3050, Victoria, Australia. behrens@wehi.edu.au
Genschel
J
J
Schmidt
R E
RE
Schmidt
H H-J
HH
D000595:Amino Acid Sequence; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy; D016333:HIV Protease / Q000235:genetics; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008060:Lipodystrophy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D007797:Laminin; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; C084098:laminin A; D016333:HIV Protease