RESEARCH LETTERS
that interfere with the cytochrome p450 metabolic pathway in
the liver (such as protease inhibitors). We saw no instances of
myopathy, rasised creatine kinase of liver enzymes, or adverse
virological events among these patients.
Until more is known about the aetiology and consequences
of lipid abnormalities in HIV-1-infected patients, our
preliminary data suggest that management of raised lipids
associated with protease inhibitors can be done carefully
following NCEP guidelines.
1
2
3
4
5
Carr A, Samaras K, Burton S, et al. A syndrome of peripheral
lipodystrophy and insulin resistance in patients receiving HIV protease
inhibitors. AIDS 1998; 12: F51–58.
Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenisis of HIV-1
protease inhibitor-associated peripheral lipodystrophy, hyperlipidemia,
and insulin resistance. Lancet 1998; 351: 1881–83.
Henry K, Melroe H, Huebesch J, et al. Coronary artery disease
associated with protease inhibitors. Lancet 1998; 351: 1328.
Kovanen PT, Mantrari M, Palosuo T, et al. Prediction of myocardial
infarction in dislipidemic men by elevated levels of immunoglobulin
casses A, E, and F, but not M. Arch Intern Med 1998; 158: 1434–39.
Danesh J, Collins R, Peto R. Chronic infections and coronary artery
disease: is there a link? Lancet 1997; 350: 430–36.
Regions Hospital HIV/AIDS Program, Regions Hospital Lipid Program, St
Paul, MN 55101–2595, USA (K Henry); University of Minnesota Medical
School, Minnesota
Protease inhibitors and adipocyte
differentiation in cell culture
AnneMarie Gagnon, Jonathan B Angel, Alexander Sorisky
Protease inhibitors are successful in the treatment of HIV-1
infection. Side-effects of excessive fat deposition, sometimes
accompanied by hyperglycaemia and hypertriglyceridaemia,
have been reported.1 Fat accumulates around the viscera and
over the neck and back. There may also be loss of fat in the
limbs and face. The mechanisms responsible for these
changes are unknown. One determinant of adipose-tissue
mass is differentiation of fibroblast-like preadipocytes into
mature adipocytes (adipogenesis). This process, once
thought to be confined to the neonatal period and childhood,
is now recognised to extend throughout life.2 Our
understanding of adipocyte differentiation has been
advanced by the use of an established preadipocyte cell line,
murine 3T3-L1 cells, which serves as a model of the in-vivo
process.3 3T3-L1 preadipocytes require insulin,
glucocorticoids (eg, dexamethasone), and a cAMP-raising
agent (eg, isobutylmethylxanthine or IBMX) to differentiate.
We investigated the effects of two protease inhibitors,
ritonavir and indinavir, on this cell line. Confluent 3T3-L1
preadipocytes were incubated for up to 8 days in
differentiation medium as described,4 in the absence or
presence of protease inhibitors at a concentration equivalent
to that found in treated people. Culture conditions limited
the differentiation to 50% of cells, allowing either inhibitory
or stimulatory effects of the drugs to be detected. Standard
assessment of adipocyte maturation included morphological
criteria (acquisition of lipid droplets staining positively with
Oil Red O) and extraction and measurement of cellular
triacylglycerol. The protease inhibitors tested enhanced
adipogenesis by as much as 10–40% (figure) and ritonavir,
for reasons unknown, may have a more potent effect.
Our data are at odds with a hypothesis by Carr and
colleagues,1 who suggested that protease inhibitors block
adipogenesis through disruption of retinoic X receptor
(RXR) action. The mechanism by which protease inhibitors
induce adipocyte differentiation is not clear. An effect of
these drugs independent of their protease-inhibitor
properties has been suggested,1 except that there may
actually be positive, rather than negative, effects of activation
1032
Murine preadipocyte cells incubated with vehicle (A) and
ritonavir (10 ␮g/mL; (B)
Stained on day 8 with Oil Red 0.
of RXR. Another possibility is that there may be proteases
that suppress adipogenesis, and which might be sensitive to
protease inhibitors. Indeed, active suppression of a gene that
encodes a fatty-acid transporter (part of the adipogenic gene
cascade) requires a protease in the preadipocyte.5 This
protease, AEBP1, contains an aminoacid sequence
KEALLTFMEQVH that has 42% identity with the 12aminoacid sequence of the HIV-1 protease used by Carr and
colleagues1 for their comparisons (KEALLDTGADDT).
Aligning the AEBP1 sequence with a single gap (KEALLTFMEQVH) strengthens the homology further to 50%
identity and 66% similarity.
Our findings suggest a possible mechanism by which
protease inhibitors may enhance adipogenesis, but caution
should be exercised in making extrapolations from these cellculture experiments on murine 3T3-L1 cells to the human
lipodystrophy syndrome. Understanding the adipogenic
action of protease inhibitors should help to make their use as
anti-HIV agents optimum while keeping side-effects on
adipose tissue, and perhaps the associated deleterious effects
of glucose and fat metabolism to a minimum.
1
2
3
4
5
Carr A, Samara K, Chisholm DJ, Cooper DA. Pathogenesis of
HIV-1-protease inhibitor-associated peripheral lipodystrophy,
hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–83.
Hirsch J, Fried SK, Edens NK, Leibel RL. The fat cell. Med Clin
North Am 1989; 73: 83–96.
Cornelius P, MacDougald OA, Lane MD. Regulation of adipocyte
development. Ann Rev Nutr 1994; 14: 99–129.
Gagnon AM, Sorisky A. Extracellular matrix induced by TGF␤
impairs insulin signal transduction in 3T3-L1 preadipose cells.
J Cell Physiol 1998; 175: 370–78.
He GP, Muise A, Li AW, Ro HS. A eukaryotic transcriptional
repressor with carboxypeptidase activity. Nature 1995; 378: 92–96.
Departments of Medicine and Biochemistry, Microbiology and
Immunology, Loeb Research Institute (A Sorisky) and OGH Research
Institute, University of Ottawa, Ottawa, Canada K1Y 4E9
THE LANCET • Vol 352 • September 26, 1998
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