ARTICLE
Auteur(s) : Claudia Ress1, Alexander
Tschoner1, Christian Ciardi1, Markus W
Laimer1, Julia W Engl1, Wolfgang
Sturm1, Helmut Weiss2, Herbert
Tilg3, Christoph F Ebenbichler1, Josef R
Patsch1, Susanne
Kaser1
1Department of Medicine I, Medical University
Innsbruck, Innsbruck, Austria
2Department of Surgery, Medical University
Innsbruck, Innsbruck, Austria
3Christian Doppler Research Laboratory for Gut
Inflammation, Department of Medicine II, Medical University
Innsbruck, Innsbruck, Austria
accepté le 30 Novembre 2009
Matrix metalloproteinases (MMPs) comprise a group of enzymes
with particular importance in extracellular matrix (ECM)
modulation. Twenty-three different MMPs, with distinct expression
patterns and functions, have been described. They are divided into
subgroups, e.g. collagenases, gelatinases and membrane-type
metalloproteinases, according to location, function and structure.
Expression levels of MMPs are very low, however, in cases of
injury, they can be upregulated in a very short time. Their
activities are regulated transcriptionally, by activation of
precursors, or by tissue inhibitors of metalloproteinases (TIMPs).
Four different TIMPs, with the ability to bind and deactivate MMP
molecules, have been described [1].
MMPs influence ECM modulation by degrading ECM components such
as collagen or gelatin, by shedding cell surface-associated
molecules, and by cleaving a wide range of proteins including other
MMPs. Subsequent activation or inactivation of the target molecules
leads to tissue breakdown, reorganization and reconstruction as
well as it supports cell-matrix and cell-cell interaction [2].
ECM modulation is involved in a variety of physiological and
pathophysiological settings: it has been shown to be essential for
several fundamental processes such as embryonic development,
inflammatory response and wound healing. Furthermore, ECM
degradation plays an important role in angiogenesis and
adipogenesis [3].
Associations between MMPs and several neurological diseases
(e.g. Alzheimer disease, multiple sclerosis), and malignancies,
particularly with tumor progression and metastasis, have been
described. Additionally, MMPs and TIMPs seem to play a major role
in development, progression and restenosis in coronary artery
disease (CAD), as well as in the expansion of aortic aneurysms and
chronic heart failure [2]. As a consequence, plasma
MMP-9 concentrations are considered to be a marker for
cardiovascular events in patients with CAD. Remarkably,
MMP-9 levels have been shown to be influenced by body weight
[4, 5].
Various studies have demonstrated an important role for MMPs and
TIMPs in adipogenesis and obesity. More specifically, distinct
expression patterns of various MMPs and TIMPs during
differentiation of 3T3-L1 adipocytes have been found.
Additionally, treatment of preadipocytes with synthetic inhibitors
of MMPs suppressed adipocyte differentiation [6, 7]. Maquoi
et al. found upregulation of MMP-3, -11, -12, -13, and
-14 and TIMP-1 mRNA expression in obese mice, whereas
expression of MMP-7, -9, -16, and -24 and TIMP-4 was
down-regulated in obesity [8]. In another study, mRNA levels of
MMP-2, MMP-3, MMP-12, MMP-14, MMP-19, and TIMP-1 were strongly
induced in adipose tissue in two genetic models of obesity and in a
diet-induced model of obesity when compared with lean littermates.
In contrast, MMP-7 and TIMP-3 mRNA expressions were
markedly decreased in obesity [6].
MMPs have also been shown to be associated with disturbances in
glucose homeostasis: Derosa et al. found increased plasma
MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in diabetics,
which may reflect abnormal extracellular matrix metabolism in
diabetes [9]. In accordance with this hypothesis, Boden et al.
reported that hyperinsulinemia in an euglycemic-hyperinsulinemic
clamp, increases MMP-2, MMP-9 and membrane type 1-MMP
activities in aortic tissues [10].
The aim of the present study was to elucidate the effect of
pronounced weight loss on MMP and TIMP serum levels. We determined
circulating serum levels of MMP-2, -3 and -7, as well as
TIMP-1, -2 and -4 levels, in morbidly obese subjects
before and one year after bariatric surgery. This design enabled us
to assess MMP and TIMP levels during a period of fundamental
metabolic change in a prospective setting.
Methods
Subjects
Eighteen morbidly obese women who underwent Swedish adjustable
gastric banding surgery were included in the study. Patients were
tested before and one year after surgery. Standard values for
MMP-7 were determined in 18, lean, healthy women (BMI range:
19-25 kg/m2, age range: 20-46 y). Subjects with
overt diabetes, other endocrinological disorders, severe renal or
hepatic disease, cardiovascular disease, malignancies, neurological
disorders, as well as subjects taking hypolipidemic,
immunosuppressive or glucose-lowering drugs were excluded from the
study. Informed consent was obtained from all study patients. The
study protocol was approved by the local ethics committee.
Laboratory measurements
Venous blood was drawn after an overnight fast and plasma or serum
was obtained by centrifugation at 3000 r.p.m. for 10 min
at 4°C immediately after blood collection. Plasma or serum samples
were either used immediately for analysis or were stored frozen at
–80 °C. Total cholesterol, high density lipoprotein
(HDL)-cholesterol (C), triglycerides (TG) and venous plasma glucose
concentrations were measured using commercially available enzymatic
kits. Fasting plasma insulin concentrations were measured by a
microparticle enzyme immunoassay on an IMx analyser (Abbott
Diagnostics, Abbott Park, IL, USA).
Serum levels of circulating MMP-2, -3 and -7, as well as
TIMP-1, -2 and -4, were determined using commercially
available, enzyme-linked immuno-sorbent assays (R&D Systems,
Wiesbaden, Germany). Insulin sensitivity was estimated by the
homeostasis model assessment (HOMA) index [11], which was
calculated by the formula:
fasting plasma glucose (mmol L−1) × fasting plasma insulin (μU
mL–1)/22·5.
Body composition
BMI was calculated as body weight in kilograms divided by height in
metres squared. Body composition (lean mass, fat mass) was
determined by impedance analysis using an InBody 3·0 Body
Composition analyser from Biospace Europe (Dietzenbach, Germany).
Measurements were taken in the morning, after an overnight fast.
Abdominal ultrasound studies
Each patient underwent abdominal ultrasonography using a
3.0 MHz curved array transducer and a standard Acuson Sequoia
512 system (Acuson, Mountain View, CA, USA) to determine the
degree of liver steatosis, as described elsewhere in detail [12].
Briefly, Level 0 was defined as a normal hepatic echo pattern,
level 1 as a slight increase in echo pattern with normal
visualization of vessels and diaphragm, level 2 as a moderate
increase in echogenicity with reduced visualisation of portal veins
and diaphragm, and level 3 as a pronounced increase in hepatic
echo pattern with poor visualisation of intrahepatic vessels and
posterior right lobe of the liver. To differentiate intra-abdominal
from subcutaneous adipose tissue accumulation, subcutaneous and
visceral fat diameters were determined as described by Pontiroli
et al. [13]. Measurements were performed in triplicate.
Statistical analysis
Differences between parameters determined before and after surgery
were calculated using Student’s paired t test. The significance of
differences in means between more than two groups was tested by
ANOVA with the Bonferroni correction. Statistical significance was
inferred at a two-tailed p-value of less than 0.05. Correlation
coefficients were calculated using Pearson’s method. Descriptive
data are expressed as means ± SD. SPSS for windows (version 11.0)
was used for statistical analysis.
Results
Clinical characteristics
Clinical characteristics of study subjects before and one year
after bariatric surgery are shown in table
1. As expected, mean BMI and waist-to-hip ratio decreased
significantly one year after bariatric surgery. The pronounced
weight reduction was mainly due to significant decreases in fat
mass, while lean mass, as determined by BIA, was reduced only
moderately. The mean decrease in the visceral fat area was more
pronounced than the decline in the subcutaneous fat area (table 1). Furthermore, the benefits of weight
loss included improvements in lipid profile and decreases in the
grade of steatosis as determined by ultrasound (grade of hepatic
steatosis: before weight loss: 1.4 ± 1.0, after weight loss: 0.8 ±
0.8, p = 0.001). Additionally, weight loss was accompanied by
improvement in glucose homeostasis. Insulin sensitivity, as
determined by the HOMA index, increased significantly after
bariatric surgery.
Table 1 Clinical characteristics of study population
before and one year after bariatric surgery
|
Before SAGB
|
1 year after SAGB
|
P-value
|
|
Age
|
34 ± 6
|
|
|
|
BMI, kg/m2
|
41.5 ± 4.1
|
34.5 ± 3.9
|
< 0.001
|
|
Waist-to-hip ratio
|
0.79 ± 0.06
|
0.77 ± 0.07
|
0.009
|
|
Fat mass, kg
|
55.9 ± 9.8
|
38.0 ± 9.1
|
< 0.001
|
|
Lean mass, kg
|
66.9 ± 8.9
|
62.8 ± 9.5
|
0.056
|
|
Subcutaneous fat diameter, cm
|
4.6 ± 1.4
|
3.5 ± 1.1
|
0.007
|
|
Intraabdominal fat diameter, cm
|
5.3 ± 2.0
|
2.1 ± 1.5
|
< 0.001
|
|
Glucose, mg/dL
|
94.8 ± 9.9
|
93.5 ± 5.3
|
0.512
|
|
Insulin, μU/mL
|
14.5 ± 5.3
|
7.6 ± 3.2
|
< 0.001
|
|
Cholesterol, mg/dL
|
181.8 ± 37.6
|
176.0 ± 32.2
|
0.457
|
|
HDL-cholesterol, mg/dL
|
50.9 ± 9.2
|
54.8 ± 10.4
|
0.030
|
|
LDL-cholesterol, mg/dL
|
107.3 ± 30.8
|
104.8 ± 28.3
|
0.724
|
|
Triglyceride, mg/dL
|
118.6 ± 38.3
|
82.4 ± 34.3
|
0.001
|
|
HOMA Index
|
3.41 ± 1.46
|
1.79 ± 0.86
|
< 0.001
|
MMP and TIMP concentrations in obese subjects
Concentrations of MMP-2, MMP-3, MMP-7, as well as of TIMP-1,
TIMP-2 and TIMP-4, were determined before and one year after
bariatric surgery. MMP-2 and MMP-3 levels remained
unchanged after significant weight loss (MMP-2: before weight loss:
182.08 ± 25.78 ng/mL, after weight loss: 180.49 ±
25.39 ng/mL; MMP-3: before weight loss: 8.65 ±
3.15 ng/mL, after weight loss: 8.97 ± 4.01 ng/mL). As
shown in figure
1, MMP-7 increased significantly with weight loss from
2.38 ± 0.42 ng/mL to 2.61 ± 0.45 ng/mL (p = 0.04). In
contrast to MMP-7, TIMP-1, TIMP-2 and
TIMP-4 concentrations were similar before and after pronounced
weight loss (TIMP-1: before weight loss: 170.61 ± 27.99 ng/mL,
after weight loss: 160.26 ± 13.62 ng/mL; TIMP-2: before weight
loss: 94.11 ± 8.67 ng/mL, after weight loss: 96.44 ±
10.02 ng/mL; TIMP-4: before weight loss 1.54 ± 0.35 ng/mL,
after weight loss: 1.67 ± 0.53 ng/mL).
MMP-7 levels in lean, healthy subjects
In order to determine standard values for circulating MMP-7 in
women, we measured its concentration in 18, lean, healthy women
(MMP-7: 3.10 ± 0.66 ng/mL, BMI: 21 ±
1.5 kg/m2, age: 29.2 ± 5.9 y). Mean
MMP-7 levels were significantly higher in lean subjects when
compared to obese subjects both before and after bariatric surgery
(p < 0.01) (lean subjects versus obese subjects before bariatric
surgery: p < 0.01 and versus obese subjects after weight
loss: p = 0.02).
Correlations
As shown in table 2A, prior to surgery,
MMP-7 serum levels correlated significantly with
intra-abdominal fat diameter, as well as with the grade of hepatic
steatosis and HDL-C. The significant correlations seen between
MMP-7 and intra-abdominal fat diameter, hepatic steatosis and
HDL-C, disappeared after bariatric surgery. MMP-3 levels
correlated with glucose levels, and circulating TIMP-1 levels
correlated with intra-abdominal fat diameter and BMI. Additionally,
TIMP-4 serum levels correlated with HDL-C.
One year after bariatric surgery, MMP-2 levels correlated
with waist-to-hip ratio, and MMP-3 serum levels correlated
with BMI and fat mass, respectively. Circulating TIMP-4 serum
levels also correlated with fat mass, and TIMP-1 serum levels
correlated with intra-abdominal fat mass (table
2B).
Table 2 Significant Pearson correlation coefficients
before (A) and after (B) weight loss
|
A)
|
|
R
|
P-value
|
|
MMP-3
|
Glucose
|
0.57
|
0.02
|
|
MMP-7
|
Intra-abdominal fat diameter
|
0.47
|
0.05
|
|
Grade of hepatic steatosis
|
0.56
|
0.02
|
|
HDL-cholesterol
|
- 0.74
|
< 0.01
|
|
TIMP-1
|
Intra-abdominal fat diameter
|
0.52
|
0.03
|
|
BMI
|
0.52
|
0.03
|
|
TIMP-4
|
HDL-cholesterol
|
0.65
|
< 0.01
|
|
B)
|
|
R
|
P-value
|
|
MMP-2
|
Waist-to-hip ratio
|
- 0.56
|
0.02
|
|
MMP-3
|
Fat mass
|
0.49
|
0.04
|
|
BMI
|
0.61
|
0.01
|
|
TIMP-1
|
Intra-abdominal fat diameter
|
0.47
|
0.05
|
|
TIMP-4
|
Fat mass
|
- 0.48
|
0.04
|
Discussion
Bariatric surgery is one of the most effective options for
achieving long-term weight loss in morbidly obese patients, and has
become a well-established model with which to study the effects of
severe obesity on metabolism, and the reversibility of these
changes. It has been shown that the beneficial effects of
pronounced weight loss as a consequence of bariatric surgery
include not just an amelioration of several metabolic parameters,
but also a significant decrease in overall mortality [14-16].
Reduced mortality in these patients might be explained by
reductions in several, well-established risk factors such as
dyslipidemia, hypertension and disturbances of glucose homeostasis.
Additionally, reduced subclinical inflammation, as well as changes
in adipocytokine pattern are thought to contribute to increased
life expectancy.
Several previous studies have revealed important roles for MMPs
and TIMPs in obesity. Determination of MMP and TIMP expression
during adipogenesis revealed distinct time-course-adjusted
expression patterns. Furthermore, animal models of diet- or
genetically-induced obesity confirmed a significant role for MMPs
and TIMPs in the differentiation of preadipocytes [6, 17-19]. In
addition to these findings, several groups have reported altered
MMP patterns in obese patients when compared with lean controls,
suggesting alterations, not only in the amount of adipose tissue,
but also in adipogenesis and ECM remodeling in obesity [20, 21].
The aim of this study was to elucidate the effect of pronounced
weight loss on serum MMP and TIMP levels in obese patients.
Recently, our group found significantly decreased MMP-9 levels
after pronounced weight loss following bariatric surgery [4].
While MMP-2, MMP-3 and TIMP-1, TIMP-2, and
TIMP-4 concentrations remained unaffected by weight loss,
MMP-7 levels were found to be significantly increased after
bariatric surgery.
MMP-7 is a protein with multifarious and partially opposing
functions. It acts as an activator of plasminogen, leads to
increased bioavailability of insulin-like growth factor 1 (IGF-1),
increases the amount of soluble tumor necrosis factor-α (TNF-α),
and is also involved in cell growth and adipocyte differentiation.
Furthermore, MMP-7 mediates vasoconstriction and
pro-inflammatory stimuli during substrate cleavage [1, 2].
Recently, Chavey et al. reported decreased MMP-7 levels
in adipose tissue of obese mice, and Maquoi et al. showed
decreased MMP-7 mRNA levels in the adipose tissue of mice fed
with a high fat diet [6, 8]. The replenishment of MMP-7 might
be one of the beneficial effects of pronounced weight loss acting
by promoting adipocyte differentiation and thus increasing the
relative number of mature adipocytes with a more favorable
adipocytokine secretion pattern. Concomitantly increased
MMP-7 might limit the extent of so-called dysfunctional
adipose tissue comprising poorly differentiated (pre)adipocytes,
which seem to play a major role in obesity-related disease [22].
The positive correlation between MMP-7 and intra-abdominal fat
mass in morbid obesity could suggest that adipose tissue is not
only a major target of MMP-7 action but also a major
determinant of MMP-7 synthesis. Remarkably, in our study we
also found that MMP-7 levels were associated with the grade of
hepatic steatosis in morbid obesity. It is well known that
development and progression of non-alcoholic, fatty liver disease
(NAFLD) is accompanied by extensive ECM remodeling [23], suggesting
that MMP-7 may play a significant role in the pathophysiology
of NAFLD. Our hypothesis is supported by data from Greco
et al. who found associations between MMP-7 gene
expression and liver fat content [24]. Additionally, Alwayn
et al. reported beneficial effects of MMP inhibition on
hepatic steatosis [25]. Our data suggest that pronounced weight
loss partially restores decreased MMP-7 levels in obesity.
However, when compared with lean, healthy women, MMP-7 levels
were still lower in weight-reduced patients. Differences might be
explained by the persistently increased amount of adipose tissue in
subjects following bariatric surgery and the lack of NAFLD in our
control group.
Among others, MMPs activities are strongly influenced by TIMPs.
The importance of the inhibition of MMPs in adipogenesis has been
shown in several studies [6, 18, 26]. In our study, TIMP levels
were unaffected by significant weight reduction. In contrast to
circulating TIMP levels, Klein et al. recently found decreased
TIMP-1 mRNA expression in liver biopsies of patients who
underwent gastric bypass surgery, suggesting tissue-specific
modulation of TIMP-1 by weight reduction without influencing
circulating TIMP-1 levels [27]. Moderately increased
TIMP-1 concentrations in obesity have been reported in two
studies [20, 28]. We thus hypothesize that oversecretion of
TIMP-1 in obesity is not reversible by weight loss.
TIMP-4 mRNA expression levels have been shown to be
decreased in obese mice. In our study, circulating
TIMP-4 remained unchanged one year after bariatric surgery,
suggesting that, similarly to TIMP-1, potential alterations of
circulating TIMP-4 levels in obesity might not be reversible
by weight loss [8, 29].
Underlining the important role of MMPs in adipose tissue, Van
Hul et al. reported that MMP-2(-/-) mice on a high
fat diet gained less weight than littermates on the same diet and
displayed hypertrophic adipocytes [30]. Additionally, a recently
published study revealed increased plasma MMP-2 levels in
obese subjects [21]. Remarkably, in our study, serum
MMP-2 levels were similar before and one year after bariatric
surgery. We conclude from our results that either alterations in
MMP-2 metabolism are irreversible in obesity, or the
contribution of adipose tissue to secreted MMP-2 was low in
these patients. Similar results were found for MMP-3 in our
study. MMP-3 exhibits proinflammatory effects by modulating
TNF-α, a pro-inflammatory cytokine that is known to be increased in
obese patients [31, 32]. On the other hand, MMP-3 seems to
exert protective effects on atherosclerotic plaques by limiting
plaque growth and enhancing plaque stability [33]. Moreover Traurig
et al. found negative correlations between
MMP-3 expression levels and body fat mass in Pima Indians
[34].
In summary, in the present study we found that serum MMP-7
levels increase with the decline of body weight, suggesting that
decreased MMP-7 levels found in obesity are reversible by
weight loss. We hypothesize that increases in MMP-7 levels
could indicate enhanced adipogenesis in subjects with pronounced
weight loss, which could explain changes in adipocytokine secretion
patterns in these patients. In contrast to MMP-7, MMP-2 and -3 and
TIMP-1, -2 and -4 levels were unaffected by weight loss.
Acknowledgments
We wish to thank BMA Simone Wühl and BMA Karin Salzmann for their
excellent assistance.
Disclosure. This work was supported by the Medizinischen
Forschungsfonds (MFF) Tirol.
References
1 Sternlicht MD and Werb Z. How matrix metalloproteinases regulate
cell behavior. Annu Rev Cell Dev Biol 2001; 17: 463.
2 Nagase H, Visse R and Murphy G. Structure and function of
matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69:
562.
3 Lemaitre V, D’Armiento J. Matrix metalloproteinases
in development and disease. Birth Defects Res C Embryo Today 2006;
78: 1.
4 Laimer M, Kaser S, Kranebitter M, et al.
Effect of pronounced weight loss on the nontraditional
cardiovascular risk marker matrix metalloproteinase-9 in
middle-aged morbidly obese women. Int J Obes (Lond) 2005; 29:
498.
5 Ye ZX, Leu HB, Wu TC, Lin SJ and Chen JW. Baseline serum
matrix metalloproteinase-9 level predicts long-term prognosis after
coronary revascularizations in stable coronary artery disease. Clin
Biochem 2008; 41: 292.
6 Chavey C, Mari B, Monthouel MN, et al.
Matrix metalloproteinases are differentially expressed in adipose
tissue during obesity and modulate adipocyte differentiation. J
Biol Chem 2003; 278: 11888.
7 Bourlier V, Zakaroff-Girard A, De Barros S,
et al. Protease inhibitor treatments reveal specific
involvement of matrix metalloproteinase-9 in human adipocyte
differentiation. J Pharmacol Exp Ther 2005; 312: 1272.
8 Maquoi E, Munaut C, Colige A, Collen D and Lijnen HR.
Modulation of adipose tissue expression of murine matrix
metalloproteinases and their tissue inhibitors with obesity.
Diabetes 2002; 51: 1093.
9 Derosa G, D’Angelo A, Scalise F, et al.
Comparison between metalloproteinases-2 and -9 in healthy subjects,
diabetics, and subjects with acute coronary syndrome. Heart Vessels
2007; 22: 361.
10 Boden G, Song W, Pashko L, Kresge K. In
vivo effects of insulin and free fatty acids on matrix
metalloproteinases in rat aorta. Diabetes 2008; 57: 476.
11 Matthews DR, Hosker JP, Rudenski AS,
Naylor BA, Treacher DF, Turner RC. Homeostasis model
assessment: insulin resistance and beta-cell function from fasting
plasma glucose and insulin concentrations in man. Diabetologia
1985; 28: 412.
12 Engl J, Sturm W, Sandhofer A, et al.
Effect of pronounced weight loss on visceral fat, liver steatosis
and adiponectin isoforms. Eur J Clin Invest 2008; 38: 238.
13 Pontiroli AE, Pizzocri P, Giacomelli M,
et al. Ultrasound measurement of visceral and subcutaneous fat
in morbidly obese patients before and after laparoscopic adjustable
gastric banding: comparison with computerized tomography and with
anthropometric measurements. Obes Surg 2002; 12: 648.
14 Bult MJ, van Dalen T, Muller AF. Surgical
treatment of obesity. Eur J Endocrinol 2008; 158: 135.
15 Sjostrom L, Lindroos AK, Peltonen M,
et al. Lifestyle, diabetes, and cardiovascular risk factors 10
years after bariatric surgery. N Engl J Med 2004; 351: 2683.
16 Adams TD, Gress RE, Smith SC, et al.
Long-term mortality after gastric bypass surgery. N Engl J Med
2007; 357: 753.
17 Lijnen HR, Van HB, Frederix L, Rio MC and Collen D. Adipocyte
hypertrophy in stromelysin-3 deficient mice with nutritionally
induced obesity. Thromb Haemost 2002; 87: 530.
18 Lijnen HR, Demeulemeester D, Van Hoef B,
Collen D, Maquoi E. Deficiency of tissue inhibitor of
matrix metalloproteinase-1 (TIMP-1) impairs nutritionally induced
obesity in mice. Thromb Haemost 2003; 89: 249.
19 Demeulemeester D, Collen D, Lijnen HR. Effect
of matrix metalloproteinase inhibition on adipose tissue
development. Biochem Biophys Res Commun 2005; 329: 105.
20 Glowinska-Olszewska B, Urban M. Elevated matrix
metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in
obese children and adolescents. Metabolism 2007; 56: 799.
21 Derosa G, Ferrari I, D’Angelo A, et al.
Matrix metalloproteinase-2 and -9 levels in obese patients.
Endothelium 2008; 15: 219.
22 Despres JP, Lemieux I. Abdominal obesity and
metabolic syndrome. Nature 2006; 444: 881.
23 Yeh MM, Brunt EM. Pathology of nonalcoholic fatty
liver disease. Am J Clin Pathol 2007; 128: 837.
24 Greco D, Kotronen A, Westerbacka J,
et al. Gene expression in human NAFLD. Am J Physiol
Gastrointest Liver Physiol 2008; 294: G1281.
25 Alwayn IP, Andersson C, Lee S, et al.
Inhibition of matrix metalloproteinases increases PPAR-alpha and
IL-6 and prevents dietary-induced hepatic steatosis and injury in a
murine model. Am J Physiol Gastrointest Liver Physiol 2006; 291:
G1011.
26 Demeulemeester D, Scroyen I, Voros G,
et al. Overexpression of tissue inhibitor of matrix
metalloproteinases-1 (TIMP-1) in mice does not affect adipogenesis
or adipose tissue development. Thromb Haemost 2006; 95: 1019.
27 Klein S, Mittendorfer B, Eagon JC, et al.
Gastric bypass surgery improves metabolic and hepatic abnormalities
associated with nonalcoholic fatty liver disease. Gastroenterology
2006; 130: 1564.
28 Kralisch S, Bluher M, Tonjes A, et al.
Tissue inhibitor of metalloproteinase-1 predicts adiposity in
humans. Eur J Endocrinol 2007; 156: 257.
29 Fernandez CA, Moses MA. Modulation of angiogenesis
by tissue inhibitor of metalloproteinase-4. Biochem Biophys Res
Commun 2006; 345: 523.
30 Van Hul M, Lijnen HR. A functional role of
gelatinase A in the development of nutritionally induced
obesity in mice. J Thromb Haemost 2008; 6: 1198.
31 Unoki H, Bujo H, Jiang M, Kawamura T,
Murakami K, Saito Y. Macrophages regulate tumor necrosis
factor-alpha expression in adipocytes through the secretion of
matrix metalloproteinase-3. Int J Obes (Lond) 2008; 32: 902.
32 Hotamisligil GS. Inflammation and metabolic disorders.
Nature 2006; 444: 860.
33 Johnson JL, George SJ, Newby AC,
Jackson CL. Divergent effects of matrix metalloproteinases 3,
7, 9, and 12 on atherosclerotic plaque stability in mouse
brachiocephalic arteries. Proc Natl Acad Sci USA 2005; 102:
15575.
34 Traurig MT, Permana PA, Nair S, Kobes S,
Bogardus C, Baier LJ. Differential expression of matrix
metalloproteinase 3 (MMP3) in preadipocytes/stromal vascular cells
from nonobese nondiabetic versus obese nondiabetic Pima Indians.
Diabetes 2006; 55: 3160.
|
Version imprimable
Version PDF
