Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance

Bastard, Jean Philippe; Caron, Michel; Vidal, Hubert; Jan, Véronique; Auclair, Martine; Vigouroux, Corinne; Luboinski, J; Laville, Martine; Maachi, Mustapha; Girard, Pierre Marie; Rozenbaum, Willy; Levan, Philippe; Capeau, Jacqueline

doi:10.1016/s0140-6736(02)08094-7

Cited by 367 publications

(315 citation statements)

References 32 publications

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“…41 We have previously observed an altered morphology and mitochondrial dysfunction in fat tissue from these HIV-infected patients. 41,42 Subcutaneous cervical adipose tissue from two lipodystrophic women aged 22 and 33 years and bearing the R482W and R439C LMNA mutations, respectively, was collected during plastic surgery. They were compared to subcutaneous abdominal adipose tissue surgical samples from two nondiabetic non-obese control women aged 20 and 42 years.…”

Section: Methodsmentioning

confidence: 87%

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: Methodsmentioning

confidence: 87%

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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“…High levels of expression of TNFa, and other cytokines such as interleukin-6 or interleukin-18 have been found in subcutaneous adipose tissue from HALS patients 14,64,85 together with similar increases in systemic levels of inflammatory cytokines such as TNFa, interleukins 1, 6, 8 and 18 and interferon-a. [86][87][88] Cytokine levels in blood correlated with viral load according to some studies.…”

Section: The Paradox Of the Common Inflammation Status In Adipose Tismentioning

confidence: 83%

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

2007

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“…Reduced plasma adiponectin may lead to reduced clearance of VLDL and IDL apoB by inhibiting lipoprotein lipase and hepatic lipase. Lipoprotein lipase mRNA has also been shown to be lower in HIV patients with lipodystrophy than in patients without lipodystrophy [13], suggesting that regulation may be at the level of transcription. In a transgenic mouse with chronically elevated adiponectin, lipoprotein lipase has been shown to be increased [14].…”

Section: Discussionmentioning

confidence: 99%

In treatment-naïve and antiretroviral-treated subjects with HIV, reduced plasma adiponectin is associated with a reduced fractional clearance rate of VLDL, IDL and LDL apolipoprotein B-100

Shahmanesh

Stolinski

et al. 2006

Diabetologia

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Aims/hypothesis: We hypothesised that loss of peripheral fat in HIV patients would result in decreased plasma adipocytokines, in particular adiponectin, and that this decrease would be associated with changes in VLDL, IDL and LDL apolipoprotein B kinetics. Methods: Plasma adiponectin, leptin and other cytokines were measured in uninfected control subjects (n=12) and three HIV-positive groups comprising treatment-naïve patients (n=15) and patients on triple antiretroviral therapy containing protease inhibitors (PI, n=15) or non-nucleoside reverse transcriptase inhibitors (NNRTI, n=25). VLDL, IDL and LDL apolipoprotein B kinetics were measured with an infusion of [1− 13 C] leucine. Regional body fat was measured with a dual energy X-ray absorptiometry scan. Insulin resistance was calculated using homeostasis model assessment (HOMA). Results: Adiponectin (median [interquartile range]) was reduced in the treatmentnaive (5.4 μg/ml [4.7-8.5]), PI (5.0 μg/ml [3.3-6.4]) and NNRTI (5.0 μg/ml [3.1-6.7]) groups compared with controls (9.7 μg/ml [6.9-13.3]) (p<0.05). In all subjects adiponectin correlated positively with HDL-cholesterol levels, the VLDL, IDL and LDL apolipoprotein B fractional clearance rates, and with the limb fat:lean body mass ratio (all p<0.01). Adiponectin correlated negatively with plasma triglyceride levels and HOMA (p<0.001).In a linear regression model that included HOMA, adiponectin was an independent predictor of VLDL and HDL-cholesterol levels and the IDL fractional clearance rate. TNF was higher in treatment-naive and PI subjects, and soluble TNF receptor superfamily, members 1A and 1B (previously known as TNF receptors 1 and 2) was higher in PI patients than in control subjects (p<0.05). Conclusions/interpretation: Adiponectin levels are significantly reduced in treated and untreated HIV patients and are predictive of VLDL and IDL apolipoprotein B fractional clearance rates. Adiponectin may have a direct effect on lipoprotein metabolism, which may be independent of insulin.

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Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance

Cited by 367 publications

References 32 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

In treatment-naïve and antiretroviral-treated subjects with HIV, reduced plasma adiponectin is associated with a reduced fractional clearance rate of VLDL, IDL and LDL apolipoprotein B-100

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