The human immunodeficiency virus (HIV1) protease inhibitor sanquinavir activates autophagy and removes lipids deposited in lipid droplets
Authors:
- A. Polus,
- M. Bociaga-Jasik,
- U. Czech,
- J. Goralska,
- U. Cialowicz,
- M. Chojnacka,
- M. Polus,
- K. Jurowski,
- A. Dembinska-Kiec
Abstract
Reduction in mortality and increased average life span of the human immunodeficiency virus (HIV)-infected patients treated with antiretroviral therapy (ART) are associated with the risk of unwanted effects, such as insulin resistance and dyslipidemia with cardiovascular complications. Antiretroviral therapy may also be associated with lipodystrophy characterized as peripheral lipoatrophy with central fat accumulation. Understanding the molecular mechanisms of lipodystrophy caused by ART is important for therapeutic strategy and the prediction of side-effects. Influence of protease inhibitor saquinavir (SQV) on preadipocyte differentiation was analyzed in in vitro human Chub-S7 cell line model. For measurement of the effects of SQV the drug was added to differentiated or non-differentiated cells. The influence of SQV on changes in the profile of gene expression was verified by microarray and changes in lipid species content were analyzed using GC-MS/MS. Results were confirmed by real-time PCR and analysis of autophagy. Addition of SQV to differentiated Chub-S7 cells lead to removal of lipids deposited in lipid droplets, down-regulation of expression of transcription factors and markers of adipocyte differentiation. Antiviral activity of SQV based on its non-selective inhibition of proteases resulted in proteasome inhibition, induction of endoplasmic reticulum stress and induction of macroautophagy. This activity was accompanied by an increase in PI, PEPL, PC lipid species especially with MUFA and PUFA. Additionally up-regulation of miR-100-3p, miR-222-5p, miR-483-5p were found, which correlated with obesity, insulin resistance, increasing insulin secretion and activation of lipolysis. Our results indicated that SQV, by inhibition of proteasome protein degradation, activated the unfolded protein response resulting in autophagic breakdown of lipids deposited in adipose tissue causing lipodystrophy.
- Record ID
- CUT93267021178a42bfb6412f336c5b25c3
- Publication categories
- ;
- Author
- Journal series
- Journal of Physiology and Pharmacology, ISSN 0867-5910, e-ISSN 1899-1505
- Issue year
- 2017
- Vol
- 68
- No
- 2
- Pages
- 283-293
- Other elements of collation
- tab.; wykr.; Bibliografia (na s.) - 291-293; Bibliografia (liczba pozycji) - 64; Oznaczenie streszczenia - Streszcz. ang.; Numeracja w czasopiśmie - Vol. 68, No 2
- Keywords in English
- adipogensis, autophagy, lipidomics, microarray, miRNA, saquinavir
- URL
- http://jpp.krakow.pl/ Opening in a new tab
- Language
- eng (en) English
- License
- Score (nominal)
- 25
- Additional fields
- Indeksowana w: Web of Science, Scopus
- Uniform Resource Identifier
- https://cris.pk.edu.pl/info/article/CUT93267021178a42bfb6412f336c5b25c3/
- URN
urn:pkr-prod:CUT93267021178a42bfb6412f336c5b25c3
* presented citation count is obtained through Internet information analysis, and it is close to the number calculated by the Publish or PerishOpening in a new tab system.