Cited by 1,065HIV-related health complications and treatmentsLipid metabolism and disordersPeroxisome Proliferator-Activated Receptors

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Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.

Carr, Andrew, Samaras, Katherine, Chisholm, Donald J, Cooper, David A·1998·The Lancet

DOI 10.1016/s0140-6736(98)03391-1

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Abstract

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome's pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.

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“ha migliorato significativamente la prognosi dei pazienti con infezione da HIV (1, 2, 3), ma negli ultimi anni i livelli di tossicità metabolica e cardiovascolare, determinati da questa categoria di farmaci, ha sollevato dubbi e perplessità sull’utilizzo costante e nel lungo periodo di queste molecole (4, 5, 6, 7).”
Background
AVALIAÇÃO DO MODELO DE HAMSTER PARA DETECÇÃO DAS ALTERAÇÕES LIPÍDICAS E CARDIOTOXICIDADE ASSOCIADAS À TERAPIA CONTRA O VÍRUS DA IMUNODEFICIÊNCIA HUMANA
Paulo, S. (2009)
Vossiuspers UvA is een imprint van Amsterdam University Press. Deze uitgave is totstandgekomen onder auspiciën van de Universiteit van Amsterdam.
Freudenthal, C. (2005)
The Association of Traditional, Non-Traditional, HIV, and Highly Active Antiretroviral Therapy-Related Risk Factors and Dyslipidemia Among People who are Living with HIV in Nova Scotia: A Longitudinal Cohort Study
Walker, K. A. (2010) · Library and Archives Canada (Government of Canada)
Dysfunkcja śródbłonka i rozwój subklinicznej miażdżycy u pacjentów zakażonych HIV z koinfekcją HCV
Barska, K. (2015)
Wpływ zespołu lipodystrofii na subkliniczną miażdżycę tętnic szyjnych u pacjentów zakażonych HIV
Drelichowska, J. (2014)
Bone dysmetabolism in HIV infection: a melting pot of opinions
Urso, R., Comandini, U. V., & Antonucci, G. (2003) · AIDS · doi:10.1097/00002030-200306130-00028
“Two pathogenetic mechanisms have been proposed to explain these results: (i) the overproduction of TNFÆ, related to HIV infection [5]; and (ii) vitamin D dysmetabolism, related to ART, via activation or suppression of retinoic acid signaling [6,7].”
Background
Manifestations rhumatologiques de l'infection par le virus de l'immunodéficience humaine
Sibilia, J., Saraux, A., & Lioté, F. (2006) · EMC - Appareil locomoteur · doi:10.1016/s0246-0521(02)00112-2
Body Composition Changes in Patients with HIV
Robinson, P. A. (2005) · AJN American Journal of Nursing · doi:10.1097/00000446-200512000-00036
Efecto de la terapia antirretroviral sobre el perfil lipídico de pacientes con Sida en Maracaibo, estado Zulia, Venezuela The Effect of Antiretroviral Therapy on the Lipid Profile of AIDS Patients in Maracaibo, State of Zulia,
Villalobos-P, R. (2010)
Veränderungen des Lipidstoffwechsels bei HIV-Patienten unter der Therapie mit Proteaseinhibitoren
Behrens, G. M. N., Schmidt, H., Genschel, J., Stoll, M., Dejam, A., Haas, R. E., Manns, M. P., & Schmidt, R. E. (2000) · Springer eBooks · doi:10.1007/978-3-642-59683-4_62
Rosuvastatina e ciprofibrato no tratamento da dislipidemia em pacientes com HIV Rosuvastatin and ciprofibrate in the treatment of dyslipidemia in patients with HIV
Domingos, H., da Cunha, R. V., Paniago, A. M. M., de Souza, A. S., Rodrigues, R. L., & Domingos, J. A. (2012) · DOAJ (DOAJ: Directory of Open Access Journals)
Efeito do tratamento clínico sobre os índices de risco cardiovascular em indivíduos infectados pelo HIV
Paulo, S. (2008)
Unerwünschte Arzneimittelreaktionen, Pathogenese, Klinik, Therapie
Bork, K. (2000) · Springer eBooks · doi:10.1007/978-3-642-59683-4_65
Proteasehemmer und Lipoproteine
Berthold, H. K., Parhofer, K. G., Rockstroh, J. K., Ritter, M. M., Addo, M. M., Wasmuth, J., Schliefer, K., & Spengler, U. (2000) · Springer eBooks · doi:10.1007/978-3-642-59683-4_61
Cardio-metabolic effects of anti-retroviral treatment in the Cape Winelands region of South Africa
Abaid, F. E. B. (2016) · SUNScholar (Stellenbosch University)

Authors: Carr, A., Samaras, K., Chisholm, D. J., & Cooper, D. A.
Affiliations: UNSW Sydney (AU)
Garvan Institute of Medical Research (AU)
Corresponding author: Carr, Andrew
ORCID: Samaras, Katherine
Chisholm, Donald J
Venue: The Lancet
Publisher: Elsevier BV
Published: 1998-06
Volume: 351
Issue: 9119
Pages: 1881-1883
ISSN: 0099-5355 (ISSN-L)
0140-6736
DOI: 10.1016/s0140-6736(98)03391-1
OpenAlex: W2171030070
Cited by: 1,065
References: 24
Citations by year: 2026: 2 · 2025: 3 · 2024: 12 · 2023: 2 · 2022: 12 · 2021: 7 · 2020: 10 · 2019: 16 · 2018: 15 · 2017: 18 · 2016: 15 · 2015: 18 · 2014: 17 · 2013: 30 · 2012: 23
FWCI: 143.69
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: The Lancet (publishedVersion)
PubMed (publishedVersion)
Funders: National Health and Medical Research Council
National Medical Research Council
Topics: Health Sciences › Medicine › Infectious Diseases › HIV-related health complications and treatments
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: HIV-1 protease inhibitors, hyperlipidemia, insulin resistance, abdominal obesity, breast hypertrophy, LRP, retinoic acid synthesis, retinoid X receptor, PPARγ, adipogenesis, adipocyte apoptosis, lipoprotein lipase, type 2 diabetes
MeSH terms: Cytochrome P-450 Enzyme System, Diabetes Mellitus, Type 2, Female, Humans, Hyperlipidemias, Insulin Resistance, Lipodystrophy, Obesity, Receptors, Immunologic, HIV Protease Inhibitors, Sequence Homology, Amino Acid, Receptors, Retinoic Acid, Low Density Lipoprotein Receptor-Related Protein-1

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Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.

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