The HIV Protease Inhibitor Indinavir Impairs Sterol Regulatory Element-Binding Protein-1 Intranuclear Localization, Inhibits Preadipocyte Differentiation, and Induces Insulin Resistance

Caron, Michel; Auclair, Martine; Vigouroux, Corinne; Glorian, Martine; Forest, Claude; Capeau, Jacqueline

doi:10.2337/diabetes.50.6.1378

Cited by 297 publications

(255 citation statements)

References 59 publications

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“…4,5,8,11 The increased amount of prelamin A in adipose tissue samples from lipodystrophic patients bearing LMNA mutations or treated with PIs indicates that prelamin A accumulation is occuring in vivo. Moreover, lipodystrophy itself could result from defective prelamin A processing, as sterol-regulatory element-binding protein-1, which contributes to adipogenesis, is sequestrated at the nuclear rim in cells with other LMNA mutations 7 and in preadipocytes chronically treated with PIs, 21 thereby impairing adipocyte differentiation. However, the role of lamin A in adipocyte differentiation is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Cell extracts prepared as described previously 21 were subjected to SDS-PAGE, blotted onto nitrocellulose membranes and probed with antibodies against lamin A/C (MAB-3211) or prelamin A (SC-6214, specific for prelamin A, and SC-7292, that recognizes both lamin A/C and prelamin A 31 ). Antibodies against p16 INK4a Cell apoptosis.…”

Section: Methodsmentioning

confidence: 99%

“…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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

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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“…9 Abnormally high SREBP-1 protein levels have been reported in adipose tissue from HALS patients in regimes containing protease inhibitors despite that SREBP1 mRNA levels were low. 14 Studies in adipocyte cell culture systems indicated an impairment in the translocation of SREBP-1 protein to the nucleus, 15 and it has been proposed that the accumulation of SREBP-1 protein in HALS patients results in fact from the accumulation of an inactive form of the protein thus explaining lipoatrophy and impaired adipogenesis. 14 However, transgenic mice overexpressing SREBP-1c show lipoatrophy, and there is no evidence that in these mice SREBP-1c accumulates in an inactive form.…”

Section: Introduction: Overview Of Adipose Tissue Disturbances In Hivmentioning

confidence: 99%

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

2007

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“…These include induction of adipocyte apoptosis [9], interference with terminal adipocyte differentiation [9,10,11], direct inhibition of the insulin-responsive glucose transporter GLUT4 [12,13,14] and interference with intracellular insulin signals leading to the deregulation of glucose and lipid metabolism [15]. None of these cellular mechanisms is necessarily mutually exclusive of the others [16,17].…”

Section: Introductionmentioning

confidence: 99%

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

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Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 µmol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated.Results. Insulin-induced interaction of phosphatidylinositol 3′-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-ζ (PKC-ζ) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-ζ to the plasma membrane.

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The HIV Protease Inhibitor Indinavir Impairs Sterol Regulatory Element-Binding Protein-1 Intranuclear Localization, Inhibits Preadipocyte Differentiation, and Induces Insulin Resistance

Cited by 297 publications

References 59 publications

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

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

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

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