Current Antiretroviral Drugs- An investigation of metabolic syndrome promotion in HepG2 cells.
Loading...
Date
2022
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Metabolic Syndrome (MetS) affects more than 20% of adults globally. Furthermore, the
prevalence of MetS in HIV-infected patients on chronic antiretroviral (ARV) therapy continues
to rise rapidly. This is alarming as a significant portion of people are HIV-infected worldwide,
with the highest incidence experienced in Sub-Saharan Africa. An estimated 21% of people
receiving ARV treatment display insulin resistance associated with mitochondrial dysfunction
and inflammation. The current study aimed to determine the disruptions of metabolic processes
associated with ARV use (Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC) and
Dolutegravir (DTG)) following a 120-h exposure period in HepG2 liver cells. Thereafter
mitochondrial stress, inflammasome activation and insulin resistance promotion were assessed.
Following HepG2 cellular ARV exposure, it was found that mitochondrial stress proteins SIRT3
and UCP2 expressions were significantly suppressed. Due to these aberrations, endogenous
cellular attempts to activate the antioxidant responses (pNrf2, SOD2, CAT) and mitochondrial
maintenance systems (PINK1 and p62) in selected singular and combinational ARV treatments
seemed insufficient. This resulted in lipid oxidative damage and reduced ATP production. These
results indicate that ARVs induce mitochondrial dysfunction in liver cells.
Furthermore, it was deduced that combinational ARV exposure promoted inflammasome
activation at a genomic level. This was seen in increased expression of NLRP3 mRNA expression
and caspase-1 activity with coinciding elevation in IL-1β in mRNA expression. Additionally, JNK
expression was upregulated, with correlating increases in p-IRS1 protein expression and
decreased IRS1 mRNA expression being observed. Consequently, both PI3K and AKT mRNA
expression was suppressed, whilst miR-128a expression was significantly upregulated.
It can be deduced that the combinational use of ARVs induced mitochondrial dysfunction and
subsequently prompted inflammasome activation. This led to dysregulation of the
IRS1/PI3K/AKT insulin signalling pathway and the initiation/promotion of insulin resistance.
This is further supported through miRNA activation, suggesting possibilities for future studies on
in vivo ARV use and related epigenetic changes.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.