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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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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