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Neue Aspekte zur Pathogenese der NASH

New aspects in the pathogenesis of NASH

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Der Gastroenterologe Aims and scope

Zusammenfassung

Die nichtalkoholische Fettlebererkrankung (NAFLD) und die nichtalkoholische Fettleberhepatitis (NASH) beschreiben ätiologisch nicht vollständig geklärte Krankheitsentitäten, für die keine gesicherte Therapie vorhanden ist. Dies ist eine medizinische Herausforderung, da ein progredienter Krankheitsverlauf von der einfachen Steatose zur Steatohepatitis mit Entwicklung einer Fibrose bis hin zur Zirrhose und zu eventueller Entstehung eines Leberzellkarzinoms beschrieben ist. Ein Überangebot von Fettsäuren, z. B. bei hochkalorischer Ernährung oder deren Freisetzung aus dem Fettgewebe, führen zur Triglyceridablagerung in den Lipidtröpfchen („lipid droplets“) der Hepatozyten. Gesättigte Fettsäuren bewirken dort ER-Stress, der über intrazelluläre Signalwege Insulinresistenz, Entzündung und Apoptose induziert (klinisches Bild der NASH). Die dafür verantwortliche intrazelluläre Schaltstelle ist das aktivierte JNK1. Die nachgeordnete Deaktivierung von FXR perpetuiert über Insulinresistenz die Lipidtröpfchenakkumulation, unterhält die Entzündung und führt zur Hyperglykämie. Apoptotischer Zelltod wird durch JNK1 unmittelbar oder durch Freisetzung von TNF-α (verstärkt durch Aktivierung von Entzündungszellen der Leber) mittelbar hervorgerufen. Neben den bekannten Signalkaskaden spielt die Aktivierung von mitochondrialer Phospholipase A2 (iPLA2) mit Freisetzung von Lysophosphatidylcholin bei der Apoptoseinduktion eine entscheidende Rolle. Zukünftige therapeutische Konzepte sollten deshalb auf Vermeidung von ER-Stress, Beibehaltung der FXR-Aktivierung und Hemmung der iPLA2 fokussieren.

Abstract

Non-alcoholic fatty liver disease (NAFLD) und non-alcoholic steatohepatitis (NASH) represent etiologically not completely understood disease entities for which an established therapy is not yet available. This is a challenge in medicine because a progressive course of the disorder from simple steatosis to steatohepatitis with development of fibrosis and finally cirrhosis with possible development of liver cancer has been described. Overload of fatty acids, e.g. by high caloric diet or release from adipose tissue, leads to triglyceride accumulation in lipid droplets of hepatocytes. Saturated fatty acids within lipid droplets cause endoplasmic reticulum (ER) stress which induces insulin resistance, inflammation and apoptosis by intracellular signal cascades (clinical features of NASH). The responsible intracellular switch is activated JNK1. The subsequent deactivation of FXR perpetuates the lipid droplet accumulation via insulin resistance, maintains inflammation and leads to hyperglycemia. Moreover, apoptotic cell death is triggered by JNK1 directly or indirectly by release of TNFα (amplified by activation of liver macrophages). Besides the involvement of defined signal cascades, the activation of mitochondrial phospholipase A2 (iPLA 2) resulting in release of lysophosphatidylcholine (LPC) is the key player for apoptosis induction. Thus, future therapeutic concepts should focus on prevention of ER stress, maintenance of FXR activation and inhibition of iPLA2 activity.

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  1. Innere Medizin IV (Gastroenterologie), Medizinische Klinik, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Deutschland

    W. Stremmel, A. Pathil-Warth & W. Chamulitrat

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  1. W. Stremmel
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  2. A. Pathil-Warth
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  3. W. Chamulitrat
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Correspondence to W. Stremmel.

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Unterstützt aus Mitteln der Dietmar-Hopp-Stiftung und der DFG.

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Stremmel, W., Pathil-Warth, A. & Chamulitrat, W. Neue Aspekte zur Pathogenese der NASH. Gastroenterologe 5, 101–107 (2010). https://doi.org/10.1007/s11377-009-0373-4

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  • DOI: https://doi.org/10.1007/s11377-009-0373-4

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