ADIPOSE TISSUE INSULIN RESISTANCE IS ASSOCIATED WITH MACROPHAGE ACTIVATION IN NON-DIABETIC PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE ...

ADIPOSE TISSUE INSULIN RESISTANCE IS
ASSOCIATED WITH MACROPHAGE ACTIVATION IN
NON-DIABETIC PATIENTS WITH NON-ALCOHOLIC
FATTY LIVER DISEASE
Milena Marietti, Chiara Rosso, Melania Gaggini, Chiara Saponaro, Konstantin Kazankov,
Emma Buzzigoli, Holger Jon Møller, Gian Paolo Caviglia, Maria Lorena Abate, Antonina
Smedile, Giorgio Maria Saracco, Hendrik Vilstrup, Jacob George, Henning Grønbæk, Amalia
Gastaldelli, Elisabetta Bugianesi

A.I.S.F., February 18-19th 2016

Chiara Rosso, MSc

La sottoscritta dichiara di non aver avuto, negli ultimi 12 mesi, conflitto
d’interesse in relazione a questa presentazione e che la presentazione
non contiene discussione di farmaci in studio o ad uso off-label

BACKGROUND
The main pathological mechanism for the onset and progression of NAFLD/NASH
is insulin resistance (IR)

BACKGROUND
 Particularly, adipose tissue IR (AT-IR) plays a crucial role in the pathogenesis of
  NASH (Bugianesi E, Diabetologia 2005; Musso G, Hepatology 2008; Gastaldelli
  A, Hepatology 2009)

 The increased flux of free fatty acids (FFAs) derived from the AT promote liver
  damage by the activation of several pathways involving lipotoxicity and oxidative
  stress

             AT-IR

                 To date, a direct pathway linking AT-IR to the
                   liver damage has not yet been described

AIM
   The aim of this study was to examine the association between IR at
        different sites and macrophages activation in a group of
          40 non-diabetic subjects with biopsy-proven NAFLD

                             METHODS
sCD163              expressed by macrophages and monocytes
                    shed from the macrophages surface into the blood during
                     their activation
                    found in the blood as soluble CD163
                    investigated as a biochemical marker of macrophages
                     activation

                   -   Holland-Fisher P, et al. Gut, 2011;
                   -   Kazankov K, et al. JGH,
                   -   Kazankov K, et al. Hepatology 2014;60:521-30
                   -   Kazankov K, et al. Scand J Clin Lab Invest, 2015

METHODS
            IR at different sites was evaluated by in vivo tracer studies

Hepatic-IR
 Endogenous glucose production (EGP) x Fasting Plasma Insulin (FPI)

Adipose Tissue IR (AT-IR)

 AT-IR1 = Ra Glycerol x FPI
 AT-IR2 = FFAs x FPI

RESULTS
Variable                          NAFLD           F

RESULTS

                                  sCD163 plasma levels shows
                                  a significant association with
                                  AT-IR

sCD163 plasma levels
correlate with either
plasma levels of FFAs
and lipolysis
(RaGlycerol) in the
adipose tissue

RESULTS
                                   sCD163 plasma
                                   levels do not
                                   correlate with Hep-IR

sCD163 plasma levels
do not correlate with
insulin and EGP by the
liver

RESULTS

RESULTS

RESULTS

                    VF      SC
AT-IR1          r   0.225   0.477
                p   0.223   0.008        VISCERAL
AT-IR2          r   0.218   0.428           FAT
                p   0.240   0.018
sCD163 (mg/L)   r   0.154   0.171
                p   0.407   0.365
                                      SUBCUTANEOUS
                                           FAT

RESULTS

      Multiple regression analysis                  Logistic regression analysis
                (F0  F4)                                      (F ≥ 2)
Variables              r      t      p      Variables           OR      95% CI       p
Gender, M           -0.166   0.1   0.947    Gender, M           0.8     0.1-10.9   0.885
BMI                  0.567   3.4   0.002    BMI                 1.5     1.1-1.9    0.009
AT-IR2               0.337   0.2   0.857    AT-IR2              0.9     0.9-1.1    0.283
CK18 Asp396 (U/L)    0.356   1.1   0.266    CK18 Asp396 (U/L)    1       0.9-1     0.866
sCD163 (mg/L)        0.589   3.7

CONCLUSIONS
 In NASH patients, macrophages activity is significantly associated with
  AT-IR
 Both AT-IR and sCD163 levels are significantly associated with fibrosis
 sCD163 levels are significantly associated with hepatic fat but not with
  VF and SF

     We hypothesize that in NAFLD, AT-IR can stimulate hepatic macrophage
     activation via an increased flux of FFAs thus concurring to liver damage.

                                                                   In vitro
                                                                  experiments

                                                                   Hepatic
                                                                  expression
                                                                  studies

ACKNOWLEDGMENTS

University of Torino, Italy      IFC-CNR, Pisa, Italy                 Aarhus University Hospital,
Prof. Elisabetta Bugianesi       Dr. Amalia Gastaldelli               Aarhus, Denmark
Dr. Milena Marietti              Dr. Melania Gaggini                  Prof. Henning Grønbæk
Dr. Maria Lorena Abate           Dr. Chiara Saponaro                  Dr. Konstantin Kazankov
Dr. Gian Paolo Caviglia          Dr. Emma Buzzigoli                   Dr. Holger Jon Møller
Dr. Antonella Olivero            Dr. Demetrio Ciociaro                Prof. Hendrik Vilstrup
Prof. Antonina Smedile
Prof. Giorgio Maria Saracco                                           University of Sydney and Westmead
                                                                      Hospital, Westmead, Australia
                                                                      Prof. Jacob George

                               Supported by the European Union's Programs FP7/2007-2013
                               under grant HEALTH-F2-2009-241762 for the project FLIP and
                               Horizon 2020 under grant 634413 for the project EPoS