ORAL PRESENTATIONS

euglycemic insulin clamp combined with (3-3H)-glucose, and

suppression of hepatic glucose production (HGP), in 117 subjects.

Results: PNPLA3 relative to b-actin expression was 2.0 (1.6–2.8)-fold

higher (p < 0.001) in AT than the liver. When related to total adipose

and liver tissue masses, PNPLA3 expression was 5.9 (5.1–8.9)-fold

higher in AT than the liver (p < 0.001). In the in vivo study, for a

given LFAT, insulin sensitivity of AT lipolysis (p < 0.05) and of HGP

(p < 0.05) were significantly higher in I148M carriers than non-

carriers.

Figure: For a given liver fat content insulin sensitivity of adiposetissue lipolysis (p < 0.05) and endogenous glucose production by insulin(p < 0.05) were significantly higher in the I148M carriers (CG+GG) vs. non-carriers (CC).

Conclusions: These data show that PNPLA3 is abundantly expressed

in AT and that increased AT lipolysis does not contribute to the

increased liver fat content in PNPLA3I148M.

O28

b7-INTEGRINS AND MADCAM-1 PLAY AN OPPOSING

ROLE DURING THE DEVELOPMENT OF NON-ALCOHOLIC

STEATOHEPATITIS (NASH)

H.K. Drescher1, A. Schippers2, S. Erschfeld1, H. Noels3, N. Wagner2,

C. Trautwein1, K. Streetz1, D.C. Kroy1. 1Department of Medicine III,2Department of Pediatrics, 3Institute of Molecular Cardiovascular

Research (IMCAR), University Hospital Aachen, Aachen, Germany

E-mail: hdrescher@ukaachen.de

Background and Aims: Non-alcoholic steatohepatitis (NASH) is

the third most common cause of chronic liver disease in western

countries and one of the fastest growing medical problems.

The relevance of infiltrating leukocytes during NASH development

remains unclear. We therefore investigated the role of the homing

receptor pair MAdCAM-1/b7 in a mouse NASH-model.

Methods: Constitutive b7-Integrin and MAdCAM-1 knockout mice

were fed MCD-diet (methionine and choline deficient) for 4 weeks.

Results: b7-deficient mice displayed an earlier and faster

progressing steatohepatitis during MCD treatment, while MAdCAM-

1-KO showed less histomorphological changes compared to

wildtype mice.

The b7-KO group displayed a stronger hepatic infiltration of

inflammatory cells, reflecting an earlier onset of NASH. Expression

of Treg markers (FoxP3, IL-2, TGFb) was significantly enhanced

in MAdCAM-1-KO mice compared to b7-Integrin deficient animals

and wildtypes, indicating a less severe disease progression in

MAdCAM-1-KO. Analysis of oxidative stress showed a stronger DHE

(Dihydroethidium)-staining in b7-KO mice and a down regulation of

transcription factors involved in the anti-oxidative stress response.

In contrast, MAdCAM-1-KO mice showed an upregulation of the

anti-oxidative stress response.

Those changes finally resulted in an earlier and stronger collagen

accumulation in b7-Integrin deficient mice, while MAdCAM-1-KO

mice were protected from fibrosis progression.

Conclusions: MAdCAM-1 and b7-Integrin deficiency leads to

opposing effects in the MCD model, with protection in MAdCAM-

1-KO animals and a more severe phenotype and significantly

stronger fibrosis progression in b7-Integrin-KO mice. Therefore, the

interaction of b7-Integrins and their receptor MAdCAM-1 provide

a potential novel target for therapeutic interventions during NASH

development.

O29

ALTERED MITOCHONDRIA IN LIVER-SPECIFIC PROHIBITIN-2 NULL

MICE INDUCES HEPATIC DAMAGES ASSOCIATED WITH STEATOSIS

AND IMPAIRED GLUCONEOGENESIS

J. Martin-Levilain1, S. Supale1, C. Merkwirth2, D. Metzger3,

P. Chambon3, T. Langer2, P. Maechler1. 1Department of Cell

Physiology and Metabolism (PHYM), University of Geneva, University

Medical Center, Geneva, Switzerland; 2Institute for Genetics, University

of Cologne, Cologne, Germany; 3Institut de Genetique et de Biologie

Moleculaire et Cellulaire, University of Strasbourg, Illkirch, France

E-mail: juliette.martin-levilain@unige.ch

Background and Aims: Regulation of mitochondrial dynamics and

functions depends on various proteins, such as prohibitins (Phb1

and Phb2). Phb dysfunctions are associated with aging, cancer,

obesity and inflammation. Mice lacking liver Phb1 exhibit hepatic

injury and hepatocellular carcinoma. The present study focused

on the role of Phb2 in liver biology and hepatic mitochondrial

function, using transgenic mice with liver-specific and time-

controlled deletion of Phb2 (Hep-Phb2−/−).

Methods: Conditional liver-specific (Alb-Cre-ERt/lox) deletion of

Phb2 was induced in 8-week old mice by sub-cutaneous

implantation of one tamoxifen pellet per animal. Mice

were sacrified 3 weeks later for plasma and liver biology

characterizations.

Table: Comparison of metabolic characteristics in Phb2f/f

Parameter Phb2fl/fl Hep-Phb2−/− p-value

Body weight (g) 24.4±3.9 15.2±1.3 0.02Liver weight (g) 1.31±0.18 0.73±0.09 0.01Plasma AST (U/L) 89.6±19.4 642.5±93.8 0.00075Plasma ALT (U/L) 33.4±3.0 246.7±40.8 0.0013Plasma bilirubin (mM) 2.33±0.13 44.6±13.4 0.032Plasma cholesterol (mM) 1.89±0.07 1.40±0.17 0.003Plasma triglycerides (mM) 1.08±0.12 0.07±0.13 0.03Glucose (mM) 5.8±0.8 3.6±0.6 0.03Hepatic glycogen (mg/mg prot) 60.3±27 23.7±5 0.05

Results: Three weeks after Tamoxifen implantation, hepatic levels

of Phb2 protein were reduced by 90%. The body and liver

weights of Hep-Phb2−/− were significantly lower compared to

control (Phb2fl/fl) mice. Electron microscopy revealed alterations in

liver mitochondrial morphology and cristae ultrastructure of Hep-

Phb2−/− mice. H&E staining showed pronounced histologic damages

in Hep-Phb2−/−, with increased lipid load. Plasma levels of AST,

S12 Journal of Hepatology 2014 vol. 60 | S1–S22