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Carcinogenesis and NAFLD
DO INFLAMMATION NETWORKS TRIGGER NASH AND
DRIVE ITS PROGRESSION?
Herbert Tilg
Department of Internal Medicine I,
Medical University Innsbruck,
Innsbruck, Austria
E-mail: herbert.tilg@i-med.ac.at
Take home messages
• Innate immunity is crucially involved in NASH pathogenesis.
• Dysregulated microbiota could reflect a starting point in the initiation of inflammation and activate
innate immune signals.
• Extrahepatic tissues, such as adipose tissue, reflect a major source of inflammatory mediators.
• Inflammatory networks drive disease progression, i.e. from steatosis to fibrosis and cancer.
Introduction
NAFLD has emerged as a major health problem throughout the world. Whereas over-nutrition
and obesity are crucially involved in the development of a simple fatty liver, it remains unclear why
approximately 10% of all affected individuals develop the ‘inflammatory’ phenotype, i.e. NASH. It
is increasingly recognized that soluble mediators synthesized by immune system cells (e.g. cytokines/
chemokines) and adipose tissue (e.g. adipocytokines) are involved in NAFLD and its progression and
also in the regulation of insulin action [1]. It has long been assumed that major triggers for the observed
liver inflammation in cases of NASH might reside in the gastrointestinal tract and a close link between
the intestinal microbiota and host metabolism has only recently been suggested [2]. The microbiota
affects metabolic processes such as energy extraction from food, and is currently believed to contribute
significantly to diseases such as obesity, T2DM, CVD and NAFLD.
Cytokines: key players in NASH
Cytokines are critically involved in the physiology of a healthy liver as well as in the pathophysiology
of many acute and chronic liver diseases (Table 1). Production of cytokines such as IL-6 and TNFα
is one of the earliest events in many types of liver injury. TNFα was the first adipocytokine found to
be associated with obesity and IR. Mice lacking TNFα or the TNF receptor had improved IS in both
dietary and genetic models of obesity [3].TNFα is able to mediate many aspects of NASH. Importantly,
weight loss has been demonstrated to result in a marked suppression of TNFα in the adipose tissue.
Expression of TNFα and its type 1 receptor is increased in patients with NASH compared to patients
with simple steatosis [4]. Small intestine bacterial overgrowth in NASH patients is associated with
increased circulating TNFα levels [5]. Furthermore, certain TNFα polymorphisms are associated
with susceptibility to IR, highlighting the importance of this cytokine in the interaction between fat
accumulation, insulin action and inflammation in humans. An important role forTNFα is also supported
by the fact that in a murine model of steatohepatitis antibody-mediated neutralization of TNFα
improves liver disease [6]. Therefore, substantial evidence exists that pro-inflammatory cytokines such
as TNFα are involved in the development of NASH. A link between the microbiota and development
84 Postgraduate Course Syllabus • Metabolic Liver Disease
DO INFLAMMATION NETWORKS TRIGGER NASH AND
DRIVE ITS PROGRESSION?
Herbert Tilg
Department of Internal Medicine I,
Medical University Innsbruck,
Innsbruck, Austria
E-mail: herbert.tilg@i-med.ac.at
Take home messages
• Innate immunity is crucially involved in NASH pathogenesis.
• Dysregulated microbiota could reflect a starting point in the initiation of inflammation and activate
innate immune signals.
• Extrahepatic tissues, such as adipose tissue, reflect a major source of inflammatory mediators.
• Inflammatory networks drive disease progression, i.e. from steatosis to fibrosis and cancer.
Introduction
NAFLD has emerged as a major health problem throughout the world. Whereas over-nutrition
and obesity are crucially involved in the development of a simple fatty liver, it remains unclear why
approximately 10% of all affected individuals develop the ‘inflammatory’ phenotype, i.e. NASH. It
is increasingly recognized that soluble mediators synthesized by immune system cells (e.g. cytokines/
chemokines) and adipose tissue (e.g. adipocytokines) are involved in NAFLD and its progression and
also in the regulation of insulin action [1]. It has long been assumed that major triggers for the observed
liver inflammation in cases of NASH might reside in the gastrointestinal tract and a close link between
the intestinal microbiota and host metabolism has only recently been suggested [2]. The microbiota
affects metabolic processes such as energy extraction from food, and is currently believed to contribute
significantly to diseases such as obesity, T2DM, CVD and NAFLD.
Cytokines: key players in NASH
Cytokines are critically involved in the physiology of a healthy liver as well as in the pathophysiology
of many acute and chronic liver diseases (Table 1). Production of cytokines such as IL-6 and TNFα
is one of the earliest events in many types of liver injury. TNFα was the first adipocytokine found to
be associated with obesity and IR. Mice lacking TNFα or the TNF receptor had improved IS in both
dietary and genetic models of obesity [3].TNFα is able to mediate many aspects of NASH. Importantly,
weight loss has been demonstrated to result in a marked suppression of TNFα in the adipose tissue.
Expression of TNFα and its type 1 receptor is increased in patients with NASH compared to patients
with simple steatosis [4]. Small intestine bacterial overgrowth in NASH patients is associated with
increased circulating TNFα levels [5]. Furthermore, certain TNFα polymorphisms are associated
with susceptibility to IR, highlighting the importance of this cytokine in the interaction between fat
accumulation, insulin action and inflammation in humans. An important role forTNFα is also supported
by the fact that in a murine model of steatohepatitis antibody-mediated neutralization of TNFα
improves liver disease [6]. Therefore, substantial evidence exists that pro-inflammatory cytokines such
as TNFα are involved in the development of NASH. A link between the microbiota and development
84 Postgraduate Course Syllabus • Metabolic Liver Disease
