Pan European Networks - Horizon 2020 - page 203

lterations in our lifestyle over the last decades, including
high caloric intake combined with a sedentary lifestyle,
have augmented the incidence of overweight and
metabolic syndrome, characterised by abdominal obesity, insulin
resistance, hypertonia and dyslipidaemia. This trend is observed in
industrialised countries (e.g. the USA or Europe). Epidemiological
data indicate that overweight and metabolic syndrome are
reaching pandemic dimensions in industrialised countries. It is
prospected that newly developing countries – as a consequence
of industrialisation and adaptation to the Western lifestyle – will
experience a steep increase in overweight and metabolic
syndrome-triggered diseases. In the past ten years, the rate of
obesity has doubled in adults and tripled in children in the USA. A
similar trend has been observed in Europe.
The liver is strongly affected by a chronic state of overweight and
metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD),
the most frequent liver disease worldwide, is the clinical
manifestation of overweight and metabolic syndrome, with 90
million cases in the USA and 40 million cases in Europe. A
significant number of NAFLD patients develop non-alcoholic
steatohepatitis (NASH), fibrosis and hepatocellular carcinoma
(HCC). Currently, HCC is the most rapidly increasing type of cancer
in the US, with a similar trend observed in Europe.We currently
lack a detailed understanding of how NASH develops and what
factors control its transition to HCC. At the same time, no
therapeutics exist to treat NASH and HCC.
In laboratory mice NASH can be induced by several different diets
such as methionine/choline-deficient diet (MCD) or choline-
deficient diet (CD) but not by a high-fat diet (HFD) alone.
However, C57BL/6 mice fed with MCD or CD do not develop
obesity or metabolic syndrome, and the diet has to be
discontinued after a few months due to weight loss and cachexia.
Thus, these approaches do not recapitulate NASH and its
consequences (e.g. transition to HCC) in humans.
Based on the clinical observations made to NASH patients that
choline deficiency in patients exacerbates NAFLD, we have
combined choline deficiency with a high-fat diet (CD-HFD) as a
chronic diet for laboratory mice, which may lead to metabolic
syndrome, steatosis, liver damage and NASH. CD-HFD-treated
mice display obesity, overweight, insulin resistance, liver damage
and fibrosis, hepatic mitochondrial damage, dyslipidaemia and
NASH, as observed in human patients (Wolf
et al., Cancer Cell,
2014). HCC developed 12 months post-CD-HFD start and
resembled histologically, genetically and morphologically human
HCC. By using this novel model we could show that adaptive
immune cells (e.g. cytotoxic T-cells as well as natural killer T cells)
greatly contribute to the diet-induced liver pathology.
Consequently, we also analysed NASH patients and patients
suffering from other liver diseases with concomitant lipid
deposition diseases (e.g. chronic hepatitis C infection) and could
find the same activated immune cells in livers of NASH patients,
as well as the same cytokines, which we identified to be causally
linked to NASH and HCC disease development. In the future the
link between activated T-cells in the liver and their crosstalk to
hepatocytes could give us important insights into how we can
generate novel therapeutics for treating NASH, as well as NASH-
induced HCC, in industrialised countries.
Wolf M J,
et al.
: Metabolic activation of intrahepatic CD8+ T cells and NKT cells
causes nonalcoholic steatohepatitis and liver cancer via cross-talk with
Cancer Cell.
2014 Oct 13;26(4):549-64. doi:
Mathias Heikenwälder
Helmholtz Zentrum München (Helmholtz-Zentrum für
Gesundheit und Umwelt (HMGU)/Technische Universität
München (TUM))
te l :
+49 89 4140 7440
The Institute of Virology explores the immune system and its link to metabolic
syndrome and non-alcoholic fatty liver disease
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