Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation

Caron, Michel; Auclair, Martine; Sterlingot, Hélène; Kornprobst, Michel; Capeau, Jacqueline

doi:10.1097/00002030-200311210-00005

Cited by 171 publications

(185 citation statements)

References 33 publications

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“…A polymorphism in the S1P/SREBP-1c gene confers a difference in risk for development of an increase in total cholesterol with PI-therapy. This suggests presence of a genetic predisposition to hyperlipoproteinemia in PI-treated patients 58 . There is also evidence that PI directly inhibit the uptake of glucose in insulinsensitive tissues, such as fat and skeletal muscle, by selectively inhibiting the glucose transporter Glut4 59 .…”

Section: Molecular Mechanisms Pi-associated Lipodystrophy and Metabolmentioning

confidence: 92%

Cardiovascular complications in the acquired immunodeficiency syndrome

Bárbaro

Silva

2009

Rev. Assoc. Med. Bras.

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Section: Molecular Mechanisms Pi-associated Lipodystrophy and Metabolmentioning

confidence: 92%

Cardiovascular complications in the acquired immunodeficiency syndrome

Bárbaro

Silva

2009

Rev. Assoc. Med. Bras.

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“…In PI-treated cells, the final concentrations of DMSO were p0.005%, below the threshold of toxicity. 19 Nevertheless, DMSO controls were performed on fibroblasts at passages 9-12, previously treated for 7 weeks or more by the solvent at 0.01% in each experiment. In FTI-treated cells, the final concentration of DMSO was 0.1%.…”

Section: Methodsmentioning

confidence: 99%

“…The HIV antiretroviral protease inhibitors (PIs) indinavir and nelfinavir impede prelamin A maturation in cultured adipocytes, 19,20 and induce nuclear alterations similar to those observed in LMNA-mutated fibroblasts. 19,21 Interestingly, these alterations occur in fibroblasts from patients with LMNA-linked lipodystrophies and premature ageing syndromes (reviewed by Mattout et al 1 ).…”

mentioning

confidence: 99%

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Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

et al. 2007

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Lipodystrophic syndromes associated with mutations in LMNA, encoding A-type lamins, and with HIV antiretroviral treatments share several clinical characteristics. Nuclear alterations and prelamin A accumulation have been reported in fibroblasts from patients with LMNA mutations and adipocytes exposed to protease inhibitors (PI). As genetically altered lamin A maturation also results in premature ageing syndromes with lipodystrophy, we studied prelamin A expression and senescence markers in cultured human fibroblasts bearing six different LMNA mutations or treated with PIs. As compared to control cells, fibroblasts with LMNA mutations or treated with PIs had nuclear shape abnormalities and reduced proliferative activity that worsened with increasing cellular passages. They exhibited prelamin A accumulation, increased oxidative stress, decreased expression of mitochondrial respiratory chain proteins and premature cellular senescence. Inhibition of prelamin A farnesylation prevented cellular senescence and oxidative stress. Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers. Thus, both LMNA mutations and PI treatment result in accumulation of farnesylated prelamin A and oxidative stress that trigger premature cellular senescence. These alterations could participate in the pathophysiology of lipodystrophic syndromes and lead to premature ageing complications. LMNA-linked lipodystrophies and progeroid syndromes form a clinical continuum of related phenotypes. 2-8 Otherwise, HIV-infected patients receiving antiretroviral therapy frequently develop a lipodystrophy syndrome associated with a high risk of metabolic and cardiovascular complications. 9 These patients also face a growing number of other agerelated comorbidities, such as neurodegeneration, osteopenia and malignancies. 10 A-type lamins are nuclear proteins required for the structural and functional integrity of the nucleus. Lamin A is translated as a protein precursor that undergoes several maturation steps, including the addition of a C-terminal farnesyl residue, which is subsequently removed by proteolytic cleavage (reviewed by Mattout et al 1 ). Defective physiological maturation of prelamin A is the main pathophysiological mechanism underlying several premature ageing syndromes, including the Hutchinson-Gilford progeria syndrome (HGPS) (reviewed by Young et al 11 ). Several studies have convincingly demonstrated that the retention of the farnesylated residue confers toxic properties to the partially processed prelamin A. 11-13 Both cellular abnormalities [14][15][16][17] and premature ageing phenotype in mice 18 are significantly improved by using drugs that inhibit prelamin A farnesylation.

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“…The PI inhibit adipogenesis and adipocyte differentiation and modify the intracellular localization of SREBP-1c [13,46]. The adjustments of SREBP-1 cause defective expression of PPAR-γ (peroxisome proliferator-activated receptor gamma) interfering in glucose metabolism [46].…”

Section: Srebp-1cmentioning

confidence: 99%

Lipodystrophic syndrome in children and adolescents infected with the human immunodeficiency virus

2008

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The introduction of highly active antiretroviral therapy (HAART) for the treatment of acquired immunodeficiency syndrome (AIDS) has resulted in greater survival of patients infected with the human immunodeficiency virus (HIV). However, the use of these drugs has been associated with lipodystrophic syndrome (LS), which is characterized by metabolic alterations (dyslipidemia, insulin resistance, diabetes, and lactic acidosis) and abnormal corporal fat distribution. Clinically, LS may manifest as three different forms: lipohipertrophy (accumulation of fat in the central part of the body), lipoatrophy (loss of fat in the extremities, face and buttocks) and mixed (lipohipertrophy + lipoatrophy). Although its physiopathology has not been elucidated, some mechanisms have been described, including leptin and adiponectin deficiency, mitochondrial dysfunction and use of antiretroviral drugs. The type, dose and duration of the antiretroviral treatment, as well as age and puberty are the main risk factors. LS is also associated with increased incidence of cardiovascular illnesses, atherosclerosis and diabetes mellitus. Treatment includes physical activity, cautious restriction of caloric intake, changes in antiretroviral therapy, and use of insulin-sensitizing and lipid-lowering agents. Follow up must be periodic, consisting of measurement of body fat distribution, evaluation of the lipid profile and insulin resistance.

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Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation

Cited by 171 publications

References 33 publications

Cardiovascular complications in the acquired immunodeficiency syndrome

Cardiovascular complications in the acquired immunodeficiency syndrome

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

Lipodystrophic syndrome in children and adolescents infected with the human immunodeficiency virus

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