Does
Efavirenz (Sustiva) Cause Lipid Accumulation in the Liver? By
Liz Highleyman
 HIV
positive patients taking antiretroviral
therapy may experience an array of metabolic complications including lipodystrophy
(body fat changes) and altered blood lipid profiles. But research has produced
conflicting data about whether these problems are due to HIV
infection itself, specific antiretroviral
medications, or perhaps a combination of known and unknown factors.
While
the thymidine analog NRTIs (stavudine
[d4T, Zerit] and zidovudine
[AZT, Retrovir]), the "d-drugs" (stavudine and didanosine
[ddI, Videx]), and protease
inhibitors have most often been linked to metabolic manifestations, the non-nucleoside
reverse transcriptase inhibitor [NNRTI] class was thought to have fewer metabolic
side effects.
But the NNRTI efavirenz
(Sustiva) may cause alterations in lipid metabolism that lead to fat accumulation
in the liver (steatosis),
according to a poster presented at the 16th Conference
on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal.
Juan
Esplugues from the University of Valencia in Spain and colleagues analyzed molecular
mechanisms that might be implicated in alterations of lipid metabolism associated
with efavirenz, as well as the role of the so-called "master switch"
of regulation of cellular bioenergetics, AMP-activated protein kinase (AMPk). 
In
this laboratory study, non-infected Hep3B cells (a liver cell line) were stained
with a fluorescent probe after 24-hour exposure to efavirenz (10, 25, or 50 mcM).
In order to characterize the nature of accumulated lipids, cells were treated
for 4 hours with efavirenz (10 and 25 mcM) and intracellular lipid content was
determined using nuclear magnetic resonance. In addition, expression of the fatty
acid transporters CD36 and FATP was analyzed using a polymerase chain reaction
assay. Selected experiments were performed in cells pretreated for 30 minutes
with an AMPk inhibitor known as Compound C. Results
Efavirenz induced neutral lipid accumulation in hepatic cells after 24-hour incubation
(124-147 mcM with efavirenz vs 106 mcM in unexposed control cells).
In the nuclear magnetic resonance experiments, the effects of efavirenz were significant
following 4-hour incubation.
The observed profile of the accumulated lipids suggested that they did not originate
in the cell membranes.
Changes in lipid accumulation related to efavirenz were not observed when fatty
acids were removed from the culture medium, demonstrating that these changes were
due to fatty acid uptake from the surrounding extracellular material.
Likewise, changes in lipid accumulation did not occur in the presence of Compound
C, suggesting that AMPk plays a key role in this lipid uptake.
The role of AMPk was also underlined by the fact that efavirenz was associated
with increased expression of CD36 and FATP mRNA, 2 of the enzyme's downstream
targets.
"Our
results demonstrate that efavirenz increases fatty acid uptake in hepatic cells,
leading to the accumulation of lipids," the investigators concluded. "These
lipids have the same chemical composition as those that form droplets."
"Given
the long-term treatment of patients with efavirenz, such effects on lipid content
suggest that this drug exerts a pro-steatotic role in the liver and could alter
lipid metabolism in this organ," they continued. "Due to the importance
of the liver in the general regulation of lipids, efavirenz may also be implicated
in some of the alterations that are characteristic of lipodystrophy."
3/13/09
Reference
A
Blas-García, D Ballesteros, D Monleón, and others. Efavirenz Causes
Accumulation of Intracellular Lipids in Hepatic Cells. 16th Conference on Retroviruses
and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009.
Abstract 718. |
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