Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations.
BACKGROUND
A 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.


OBJECTIVE
A possible inhibition of SREBP-1c-dependent genes by the protease inhibitor indinavir and its possible reversal by the lipid-lowering drug simvastatin were studied.


METHODS
The 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.


RESULTS
Indinavir inhibited the SREBP-1c-dependent genes encoding the lipoprotein lipase (103 nmol/l resulted in an inhibition of 12.4%; P = 0.0051) and the fatty acid synthase (103 nmol/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.


CONCLUSIONS
Indinavir inhibits important effector genes of the SREBP-1c pathway, explaining major HAART-related adverse effects.
Miserez
André R
AR
Cardiovascular Genetics, Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel, Basel, Switzerland.
Muller
Patrick Y
PY
Spaniol
Violeta
V
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D064429:Fatty Acid Synthases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000235:genetics*; D019821:Simvastatin / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D017320:HIV Protease Inhibitors; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D019469:Indinavir; D019821:Simvastatin; D064429:Fatty Acid Synthases; D008071:Lipoprotein Lipase