POSTERS
Results: Infiltration of pro-inflammatory macrophages into
epididymal white adipose tissue (eWAT), assayed by immunohis-
tochemistry staining for F4/80+ crown-like structures, was reduced
in treated mice compared to placebo mice. Despite the similarity
in body weight, treated mice showed a decrease in terminal blood
glucose levels compared to placebo mice (P = 0.0037). Interestingly,
IDN-6556 treatment resulted in improved insulin function as
measured by plasma insulin ELISA versus placebo (0.23±0.089 vs.
0.97±0.26ng/ml, P = 0.023). We examined the inhibition of caspase
proteins by IDN-6556 in the eWAT and saw significant reduction
in apoptosis in the treated versus the placebo group (P = 0.0072).
In addition, IDN-6556 also caused decreased hepatic steatosis in
treated mice compared to placebo mice. We concluded that IDN-
6556 treatment ameliorated insulin resistance in HFD-fed mice
and attenuated inflammation as measured by diminished levels
of adipocyte macrophage infiltration. Furthermore, we observed
that the pan-caspase inhibitor reduced apoptosis in the eWAT and
improved hepatic steatosis in diet-induced obesity.
1297
IL12 IS DOWN REGULATED IN OBESE CHILDREN WITH NAFLD
AND UPREGULATED IN SIMPLE OBESITY
J. Michalkiewicz1, P. Socha2, A. Wierzbicka-Rucinska3,
P. Pludowski3, L. Gackowska4, I. Kubiszewska4, J. Trojanek1,
W. Janczyk5, M. Szalecki6, M. Litwin7. 1Clinical Microbiology
and Immunology, Children’s Memorial Health Institute, Warsaw,2Gastroenterology, Hepatology and Eating Disorders, 3Biochemistry
and Experimental Medicine, Children’s Memorial Health Institute,
Warszawa, 4Dep. of Immunology, Collegium Medicum Nicolaus
Copernicus University, Bydgoszcz, 5Gastroenterology, Hepatology
and Eating Disorders, 6Endocrinology, 7Nephrology and Arterial
Hypertension, Children’s Memorial Health Institute, Warsaw, Poland
E-mail: [email protected]
Introduction and Objectives: Non-alcoholic fatty liver diseases
(NAFLD) represents a complex of inflammatory changes in
the liver ranging from asymptomatic steatosis with increased
aminotransferase levels to non-alcoholic steato-hepatitis (NASH)
and cirrhosis. The cellular mechanisms responsible for induction
of different forms of liver inflammation are largely unknown.
Therefore we tested concentrations of inflammatory mediators
in serum (cytokines, soluble cellular receptors) in children with
NAFLD, obesity and healthy controls.
Methods: The study included: 53 NAFLD children, 31 aged matched
obese children without NAFLD, and 39 age matched healthy
children as a control group, with mean age of 13 years. The
serum concentrations of inflammatory mediators: MMP-9, TIMP-1,
IL-1beta, IL-12p70, IL-6, TNF-alpha, sCD14, (soluble form of CD14
receptor), and TREM (Triggering receptor expressed on myeloid
cells-1) were assessed by ELISA. Body mass composition and bone
age were evaluated by DEXA (dual-energy X-ray absorptiometry).
Results: Obese children did not differ from the NAFLD group in
BMI-Z scores. Obese NAFLD children were characterized by:
a. elevated levels of MMP-9, TIMP-1, IL 1-beta and sCD14, decreased
TNF-alpha and similar levels of IL12p7-in comparison with
healthy children,
b. decreased IL12p70 in NAFLD when compared to obesity group,
c. lack of correlation between mediator level and lipids parameters,
d. negative correlation between TREM-1 and GGTP, and positive
correlations between: MMP-9 vs bone age, and IL1-beta vs.
total body bone mineral density, lean body mass and fat mass.
Additionally, sCD14 correlated positively with the android type
of obesity.
Conclusion: NAFLD is associated with upregulation of many
parametres of inflammatory response (sCD14, MMP-9, TIMP-1,
Il 1beta). Surprisingly however, Il12p70 was down regulated in
children with NAFLD when compared to obese age matched
controls, remaining similar as in healthy controls. It may indicate
that obesity related inflammation in NAFLD children results in
monocyte/macrophage inhibition in the course of the disease
(antiinflammatory response mediated by Il12 blocking fibrotic
cytokines?).
1298
TARGETING PPARS BY BEZAFIBRATE ALLEVIATES OBESITY, NAFLD
AND INSULIN RESISTANCE DUE TO MATERNAL OBESITY IN MICE
V. Souza-Mello, D.C. Magliano, T.C.L. Bargut, M.B. Aguila,
C.A. Mandarim-de-Lacerda. Department of Anatomy, State University
of Rio de Janeiro, Rio de Janeiro, Brazil
E-mail: [email protected]
Background and Aims: Diet-induced maternal obesity yields an
overweight phenotype, with insulin resistance and non-alcoholic
fatty liver disease (NAFLD) in the offspring. This study aimed to
evaluate whether activation of peroxisome proliferator-activated
receptor (PPAR)a and PPARg by Bezafibrate (BZ) could attenuate
obesity and NAFLD in male offspring from obese C57BL/6 dams.
Methods: Females were fed on a SC (standard chow; 10% lipids)
diet or HF (high-fat, 49% lipids) diet for 8 weeks before mating
and during gestation and lactation periods. Male offspring were
weaned onto a SC diet and subdivided into 4 groups: SC, SC/BZ,
HF and HF/BZ. Treatment with Bezafibrate started at 12th week and
was maintained for 3 weeks. Bezafibrate was added to the diets
at the dose of 100mg/kg. Metabolic measurements, biochemical
analysis, stereological tools and immunoblotting were performed.
Results: The HF diet yielded an overweight phenotype and an
increase in oral glucose tolerance and fasting glucose of dams.
The HF offspring presented noticeable body mass gain, high levels
of plasmatic and hepatic TG, high levels of pro-inflammatory and
low levels of anti-inflammatory adipokines, impairment of glucose
metabolism, different fat pad mass distribution, a greater amount
of larger adipocytes, hepatic steatosis, high expression of lipogenic
proteins concomitant to decreased expression of PPARa in liver, and
diminished expression of PPARg and adiponectin in white adipose
tissue (WAT). Inversely, treatment with Bezafibrate ameliorated
hepatic outcomes generated by maternal obesity as well as WAT
remodeling, with improvement of structural, biochemical and
molecular data of animals’ livers and epididymal WAT. NAFLD was
completely reversed by the treatment due to due to increased
PPARa/PPARg ratio, which favours beta-oxidation and counters
lipogenesis.
Conclusion: Diet-induced maternal obesity lead to alterations in
metabolism, hepatic lipotoxicity and adverse liver and adipose
tissue remodeling caused in the offspring. Targeting PPAR by
Bezafibrate has beneficial effects reducing hepatic alterations.
In addition, Bezafibrate could be used to reverse the WAT
inflammatory state through PPARgamma activation.
Acknowledgements: CNPq (Brazilian Council of Science and
Technology, www.cnpq.br), grant number 470727/2009–8 for CAML
and FAPERJ (Rio de Janeiro State Foundation for Scientific Research,
www.faperj.br), grant number E-26/102.289/2010 for VSM.
1299
PHOSPHOLIPASE A2 CONTROLS THE MEMBRANE FATTY
ACID UPTAKE COMPLEX IN HEPATOCYTES: A POTENTIAL
THERAPEUTIC TARGET IN NASH
W. Stremmel1, S. Staffer2. 1Internal Medicine IV, 2University Clinics
of Heidelberg, Heidelberg, Germany
E-mail: [email protected]
Background: The mechanism by which fatty acids are taken up,
i.e. by hepatocytes, and how this is regulated remains unclear.
Uncontrolled fat accumulation within the liver leads to steatosis
and non alcoholic steatohepatitis (NASH) which are serious threats
to health in Western populations. In mice models of NASH it
S524 Journal of Hepatology 2013 vol. 58 | S409–S566
