Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation.
OBJECTIVE
To study whether HIV protease inhibitors could induce nuclear lamina alterations in adipocytes as observed in a genetic form of lipodystrophy due to lamin A/C mutation.


METHODS
We have previously observed that indinavir (IDV) impairs adipocyte differentiation and sterol regulatory element-binding protein-1 (SREBP-1) nuclear localization in 3T3-F442A adipocytes. We compared here the effects of IDV with that produced by two other PIs, nelfinavir (NFV) and amprenavir (APV) on adipose conversion, cellular localization of SREBP-1, nuclear morphology, and maturation and stability of the lamina network.


RESULTS
IDV and NFV, but not APV, altered adipose cell differentiation, as shown by lipid staining and protein expression of SREBP-1, CAAAT/enhancer binding protein (C/EBP)alpha and fatty acid synthase (FAS). In IDV-treated cells, 50-60 % of the nuclei could not accumulate SREBP-1. Twenty percent of these SREBP-negative nuclei were grossly dysmorphic, with blebs and prominent herniations, and showed an altered distribution of lamin A/C and lamin B. In IDV-treated cells, nuclear fragilization was shown by the abnormal extractibility of lamina proteins and SREBP-1, and the accumulation of prelamin A. NFV similarly altered lamin A/C maturation whereas APV was almost ineffective.


CONCLUSIONS
We show in an adipose cell line that IDV and NFV induced alterations at the nuclear level by promoting defects in lamin A/C maturation, organization and stability. We suggest that these lamina network alterations might be responsible for SREBP-1 nuclear mislocalization therefore resulting in altered adipocyte differentiation.
INSERM U. 402, Faculté de Médecine Saint-Antoine, Paris, France.
Martine
M
Caron
Martine
M
Auclair
Hélène
H
Sterlingot
Michel
M
Kornprobst
Jacqueline
J
Capeau
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002219:Carbamates; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005663:Furans; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D019469:Indinavir / Q000494:pharmacology; D034904:Lamin Type A / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D019888:Nelfinavir / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D002219:Carbamates; D004268:DNA-Binding Proteins; D005663:Furans; D017320:HIV Protease Inhibitors; D034904:Lamin Type A; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014157:Transcription Factors; C440308:lamin C; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir