Endoplasmic Reticulum Stress Links Dyslipidemia to Inhibition of Proteasome Activity and Glucose Transport by HIV Protease Inhibitors

The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently descr...

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Bibliographic Details
Published in:Molecular pharmacology 2005-06, Vol.67 (6), p.1909-1919
Main Authors: Parker, Rex A, Flint, Oliver P, Mulvey, Ruth, Elosua, Carolina, Wang, Faye, Fenderson, William, Wang, Shulin, Yang, Wen-Pin, Noor, Mustafa A
Format: Article
Language:English
Subjects:
Animals
Cell Line
Dose-Response Relationship, Drug
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - enzymology
Endoplasmic Reticulum - genetics
Endoplasmic Reticulum - metabolism
HIV Protease Inhibitors - pharmacology
Human immunodeficiency virus
Humans
Hyperlipidemias - enzymology
Hyperlipidemias - genetics
Hyperlipidemias - metabolism
Mice
Monosaccharide Transport Proteins - antagonists & inhibitors
Monosaccharide Transport Proteins - metabolism
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors
Rats
Rats, Wistar
Stress, Physiological - genetics
Stress, Physiological - metabolism
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Summary:The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, time-dependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.104.010165