Lopinavir co-induces insulin resistance and ER stress in human adipocytes

Autor: Mansour Djedaini, Annie Ladoux, Cedric Darini, Milou-Daniel Drici, Perla Saint-Marc, Christian Dani, Pascal Peraldi
Přispěvatelé: Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Rok vydání: 2009
Předmět:
MESH: Eukaryotic Initiation Factor-2
Glucose uptake
Eukaryotic Initiation Factor-2
Endoplasmic Reticulum
Biochemistry
Lopinavir
Salubrinal
chemistry.chemical_compound
0302 clinical medicine
Adipocytes
Phosphorylation
[SDV.BDD]Life Sciences [q-bio]/Development Biology
0303 health sciences
Thiourea
MESH: Insulin Receptor Substrate Proteins
3. Good health
MESH: Insulin Resistance
030220 oncology & carcinogenesis
medicine.drug
medicine.medical_specialty
Biophysics
MESH: Pyrimidinones
Pyrimidinones
Biology
Cell Line
Dephosphorylation
MESH: Thiourea
03 medical and health sciences
Insulin resistance
MESH: Endoplasmic Reticulum
Internal medicine
medicine
Humans
Molecular Biology
MESH: Adipocytes
030304 developmental biology
MESH: HIV Protease Inhibitors
MESH: Humans
MESH: Phosphorylation
Cell Biology
HIV Protease Inhibitors
medicine.disease
IRS1
MESH: Cell Line
MESH: Cinnamates
Endocrinology
chemistry
Cinnamates
Unfolded protein response
Insulin Receptor Substrate Proteins
Insulin Resistance
Zdroj: Biochemical and Biophysical Research Communications
Biochemical and Biophysical Research Communications, Elsevier, 2009, 386 (1), pp.96-100. ⟨10.1016/j.bbrc.2009.05.148⟩
ISSN: 1090-2104
0006-291X
Popis: International audience; HIV-protease inhibitors (PIs) markedly decreased mortality of HIV-infected patients. However, their use has been associated with occurence of metabolic abnormalities the causes of which are not well understood. We report here that lopinavir, one of the most prescribed PI, dose-dependently co-induced insulin resistance and ER stress in human adipocytes obtained from differentiation of precursor cells. Insulin resistance was subsequent to IRS1 phosphorylation defects and resulted in a concentration-dependent decrease of glucose uptake. The major ER stress pathway involved was the phosphorylation of eIF2-alpha. Salubrinal, a selective eIF2-alpha dephosphorylation inhibitor, induced insulin resistance by targeting IRS1 phosphorylation at serine 312 and acted synergistically with LPV when both drugs were used in combination. This study points out the key role of eIF2-alpha phosphorylation in the development of PI-associated insulin resistance and ER stress. Thus, this protein represents a promising therapeutic target for development of new PIs devoid of adverse metabolic effects.
Databáze: OpenAIRE
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