Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations
作者:
André Miserez,
Patrick Muller,
Violeta Spaniol,
期刊:
AIDS
(OVID Available online 2002)
卷期:
Volume 16,
issue 12
页码: 1587-1594
ISSN:0269-9370
年代: 2002
出版商: OVID
关键词: retrovirus;antiretroviral therapy;protease inhibitors;hyperlipidaemia;lipodystrophy;sterol-regulatory element-binding protein;SREBP;reporter gene assays
数据来源: OVID
摘要:
BackgroundA syndrome characterized by hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia, and lipodystrophy has been found to be associated with highly active antiretroviral treatment (HAART) including protease inhibitors. A marker predicting this syndrome has been previously identified in the gene encoding the sterol-regulatory element-binding protein (SREBP)-1c, a regulator of triglycerides, cholesterol, insulin, and adipocytes.ObjectiveA possible inhibition of SREBP-1c-dependent genes by the protease inhibitor indinavir and its possible reversal by the lipid-lowering drug simvastatin were studied.MethodsThe effects of indinavir and simvastatin on the inhibition/activation of SREBP-1c-dependent genes were compared with the effects of indinavir and simvastatin on the inhibition/activation of SREBP-1c-independent genes.ResultsIndinavir inhibited the SREBP-1c-dependent genes encoding the lipoprotein lipase (103nmol/l resulted in an inhibition of 12.4%;P= 0.0051) and the fatty acid synthase (103nmol/l resulted in an inhibition of 30.3%;P= 0.036) in a dose-dependent fashion but not the SREBP-1c-independent gene encoding the low-density lipoprotein receptor. Simvastatin antagonized the indinavir-induced SREBP-1c-inhibition.ConclusionsIndinavir inhibits important effector genes of the SREBP-1c pathway, explaining major HAART-related adverse effects.
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